Marc A. Bjurlin, DO, MSc
- Assistant Professor, Urology
- New York University
Animal models have shown that fatty acid overload results in intramyocardial triglyceride accumulation infection 4 weeks after miscarriage buy 250 mg ampicillin with visa, cellular lipotoxicity bacteria zapper for face cheap ampicillin 500mg amex, and impairment in cardiac energy metabolism virus download buy cheap ampicillin 250mg online. The available studies do not imply causality but suggest that accumulation of myocardial triglyceride may be at least an indirect marker of early cardiac dysfunction virus and trip purchase 250 mg ampicillin. We cannot exclude the possibility that cardiac fat is simply a consequence of fatty acid overload antimicrobial washcloth discount ampicillin 500 mg line, progressing more rapidly after saturation of the cardiac muscle oxidative capacity infection under toenail buy 500 mg ampicillin fast delivery. Indeed, in patients with dilated cardiomyopathy there is a preferential utilization of carbohydrates, probably due to an impairment in fatty acid oxidation, a reduced blood flow, a lower oxygen consumption at rest, and an impaired ability to increase glucose uptake during stress. Known locations of perivascular adipose tissue include the aorta (periaortic adipose tissue) and the microvascular beds of the mesentery, muscle, kidney, and adipose tissue. For a long time, perivascular fat was considered to provide mechanical support for any blood vessel it surrounds. Recent studies, however, have clearly shown that these adipocytes are an important source of adipocytokines as well as typical inflammatory cytokines, which regulate vascular function. It was recently proposed that the role of perivascular fat in the regulation of vascular function might be mediated by the central nervous system, which regulates adipose tissue metabolism and adipocytokine release. Thus, there is now a compelling need to quantify ectopic fat accumulation not only for diagnostic purposes but also for therapeutic interventions with weight reduction, drugs, or pharmaceuticals targeted to adipose tissue, as well as antiobesity medications. Automatic quantification of subcutaneous and visceral adipose tissue from whole-body magnetic resonance images suitable for large cohort studies. Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample: the Framingham Heart Study. Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study. Visceral fat in hypertension: Influence on insulin resistance and beta-cell function. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Echocardiographic epicardial adipose tissue is related to anthropometric and clinical parameters of metabolic syndrome: A new indicator of cardiovascular risk. Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. On the positive side, it provides a safe repository for excess calories and glucose. On the negative side, it impairs the ability of body tissues to respond to insulin and can lead to mitochondrial dysfunction and impairment in energy production. The balance between the two sides may differ among subjects, but is influenced by age, gender, and ethnicity, thereby influencing individual disease risk. Ethnic differences in pancreatic fat accumulation and its relationship with other fat depots and inflammatory markers. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: Pathophysiology and clinical implications. Increased mediastinal fat and impaired left ventricular energy metabolism in young men with newly found fatty liver. Reversal of type 2 diabetes: Normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol. Adipose tissue in the mammalian heart and pericardium: Structure, foetal development and biochemical properties. Determination of triglyceride in the human myocardium by magnetic resonance spectroscopy: Reproducibility and sensitivity of the method. Weight change modulates epicardial fat burden: A 4-year serial study with non-contrast computed tomography. Substantial changes in epicardial fat thickness after weight loss in severely obese subjects. Effects of weight loss after bariatric surgery on epicardial fat measured using echocardiography. Prolonged caloric restriction in obese patients with type 2 diabetes mellitus decreases myocardial triglyceride content and improves myocardial function. Epicardial fat from echocardiography: A new method for visceral adipose tissue prediction. Left ventricular diastolic function in type 2 diabetes mellitus is associated with myocardial triglyceride content but not with impaired myocardial perfusion reserve. Triacylglycerol lipases and metabolic control: Implications for health and disease. Systemic resistance to the antilipolytic effect of insulin in black and white women with visceral obesity. Pancreatic fat is negatively associated with insulin secretion in individuals with impaired fasting glucose and/or impaired glucose tolerance: A nuclear magnetic resonance study. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. Vascular lipotoxicity: Endothelial dysfunction via fatty-acid-induced reactive oxygen species overproduction in obese Zucker diabetic fatty rats. Inhibition of the renin-angiotensin system prevents free fatty acid-induced acute endothelial dysfunction in humans. Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Effects of free fatty acids on gluconeogenesis and autoregulation of glucose production in type 2 diabetes. Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: A quantitative study. Separate contribution of diabetes, total fat mass, and fat topography to glucose production, gluconeogenesis, and glycogenolysis. Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: Sites and mechanisms. Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Fatty liver index is associated with insulin resistance, risk of coronary heart disease and early atherosclerosis in a large European population. Alanine aminotransferase predicts coronary heart disease events: A 10-year follow-up of the Hoorn Study. Hepatic steatosis is associated with an increased risk of carotid atherosclerosis. Evaluation of metabolic syndrome frequency and carotid artery intima-media thickness as risk factors for atherosclerosis in patients with nonalcoholic fatty liver disease. Nonalcoholic fatty liver disease is associated with carotid atherosclerosis: A casecontrol study. The natural history of nonalcoholic fatty liver disease: A population-based cohort study. Ectopic fat storage in the pancreas, liver, and abdominal fat depots: Impact on beta-cell function in individuals with impaired glucose metabolism. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: Evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Intramyocellular triglyceride content is a determinant of in vivo insulin resistance in humans: A 1H-13C nuclear magnetic resonance spectroscopy assessment in offspring of type 2 diabetic parents. Determinants of intramyocellular triglyceride turnover: Implications for insulin sensitivity. Increased intramuscular lipid storage in the insulin-resistant and endurance-trained state. Properties of skeletal muscle mitochondria isolated from subsarcolemmal and intermyofibrillar regions. Increased subsarcolemmal lipids in type 2 diabetes: Effect of training on localization of lipids, mitochondria, and glycogen in sedentary human skeletal muscle. The ventricular epicardial fat is related to the myocardial mass in normal, ischemic and hypertrophic hearts. Epicardial adipose tissue: Anatomic, biomolecular and clinical relationships with the heart. Proinflammatory phenotype of perivascular adipocytes: Influence of high-fat feeding. Long-term beneficial effect of a 16-week very low calorie diet on pericardial fat in obese type 2 diabetes mellitus patients. Epicardial adipose tissue as new cardio-metabolic risk marker and potential therapeutic target in the metabolic syndrome. Myocardial triglyceride content and epicardial fat mass in human obesity: Relationship to left ventricular function and serum free fatty acid levels. Short-term hyperinsulinemia and hyperglycemia increase myocardial lipid content in normal subjects. Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy. Perivascular adipose tissue from human systemic and coronary vessels: the emergence of a new pharmacotherapeutic target. Perivascular adipose tissue and its role in type 2 diabetes and cardiovascular disease. Perivascular adipose tissue as a messenger of the brain-vessel axis: Role in vascular inflammation and dysfunction. Paracrine regulation of vascular tone, inflammation and insulin sensitivity by perivascular adipose tissue. In the reference male (75 kg), approximately 40% of body mass is skeletal muscle, whereas in the reference female (58 kg), this tissue contributes approximately 29% of total body mass. Even with severe obesity, muscle contributes approximately 25% of total body weight. Skeletal muscle, by virtue of its predominance and capacities for energy production and storage, can therefore dramatically influence whole-body metabolism. This chapter describes alterations in protein, carbohydrate, and lipid metabolism that are evident in skeletal muscle with obesity. It also discusses how muscle in and of itself sends signals through myokines that can influence substrate utilization and storage. In a classic study by Forbes, the amount of lean body mass plotted against fat mass formed a logarithmic curve,5 meaning that as fat mass increased, lean mass increased in smaller and smaller increments. One possible explanation for this relationship is that the increased body mass associated with obesity places a greater load on skeletal muscle and therefore imparts a training effect (analogous to resistance training) to increase muscle mass and strength. Evidence in support of this is that maximal leg and trunk strength, but not handgrip and arm strength, has been shown to be greater in obese than in lean individuals. The energy cost of protein synthesis, which scales with muscle mass, is estimated to range from 485 kcal/day in a young male to 120 kcal/day in an elderly woman. The reason for the differences between studies is not clear but may be related to how data are normalized, as protein kinetics on an absolute whole-body basis are always greater with obesity. Under insulin-stimulated conditions, whole-body protein synthesis has been shown to be decreased with obesity14,21 or the same. In obese individuals, whole-body protein degradation rate has been found to be the same14,20,24,25 or higher. Unfortunately, direct measures of muscle-specific protein degradation are lacking. With these findings, it is tempting to conclude that the skeletal muscle of obese individuals cannot respond to physiological cues to modify rates of protein metabolism. This lack of "metabolic flexibility," which is defined as appropriately altering energy utilization in response to changes in fuel availability,29 is akin to conditions seen in 22. Insulin action in muscle starts with binding of insulin and subsequent activation of intrinsic tyrosine kinase in the beta subunit of the insulin receptor (Figure 22. The insulin receptor phosphorylates a number of intracellular proteins on tyrosine residues to initiate the signaling process. To investigate mechanisms of insulin resistance, a strip preparation was developed in rectus abdominus muscle removed during elective surgery. Using this in vitro system, it was confirmed that insulin stimulation of glucose uptake, glycolysis, glucose oxidation, and glycogen synthesis are depressed in muscle of obese individuals,30,31 as had been reported for in vivo metabolism. Likewise, the tyrosine kinase activity of partially purified insulin receptor was depressed in muscle with obesity. It was concluded that insulin resistance is a result of depressed insulin signal transduction. Myoblasts are then put into a medium that induces differentiation to myotubes (elongated, multinucleated cells with many characteristics of mature muscle tissue). Because all of the steps of the insulin signaling pathway are depressed in muscle of obese individuals, it was speculated that the most proximal step might be the point where control is exerted. This was confirmed by decreased activity of partially purified muscle insulin receptors from obese people. Activation of these kinases may be the mechanism that terminates the insulin signal and also causes insulin resistance during long periods of high fasting insulin, that is, hyperinsulinemia. There is a direct relationship between hyperinsulinemia and insulin resistance, but a cause-and-effect relationship has not been established.
This is especially concerning given that so many overweight and obese children are vulnerable to victimization on a daily basis without sufficient support antibiotics in pregnancy order ampicillin line, coping strategies infection after sex purchase ampicillin line, or intervention virus x aoba x trip discount ampicillin 250mg visa. The national obesity research agenda must include attention to weight bias so that efforts can begin to change 468 Handbook of Obesity 20 infection next to fingernail best ampicillin 250mg. Territory assignment decisions and supervising unethical selling behavior: the effects of obesity and gender as moderated by job-related factors antibiotics simplified pdf buy ampicillin with mastercard. Obesity antibiotic resistance quizlet purchase ampicillin 250 mg amex, attractiveness, and differential treatment in hiring: A field experiment. The effects of a stated organizational policy on inconsistent disciplinary action based on salesperson gender and weight. Obesity and the workplace: Current programs and attitudes among employers and employees. Perceptions of weight discrimination: Prevalence and comparison to race and gender discrimination in America. Confronting and coping with weight stigma: An investigation of overweight and obese adults. The impact of obesity on gynecologic cancer screening: An integrative literature review. Thin is "in" and stout is "out": What animated cartoons tell viewers about body weight. Obesity in the news: Do photographic images of obese persons influence anti-fat attitudes Headless, hungry, and unhealthy: A video content analysis of obese persons portrayed in online news. Weight-based victimization toward overweight adolescents: Observations and reactions of peers. Weight-teasing among adolescents: Correlations with weight status and disordered eating behaviors. Prevalence, characteristics, and correlates of teasing experiences among overweight children vs. Weight-based victimization among adolescents in the school setting: Emotional reactions and coping behaviors. Beliefs and attitudes about obesity among teachers and school health care providers working with adolescents. Implicit anti-fat bias in physical educators: Physical attributes, ideology, and socialization. Just as smart but not as successful: Obese students obtain lower school grades but equivalent test scores to nonobese students. Parents and vehicle purchases for their children: A surprising source of weight bias. Associations between perceived weight discrimination and the prevalence of psychiatric disorders in the general population. Clinical Obesity and Related Metabolic Disease in Adults and Children: Blackwell Publishing Ltd. Social, educational, and psychological correlates of weight status in adolescents. Gender and ethnic differences in obesity-related behaviors and attitudes in a college sample. Weightbased stigmatization, psychological distress, and binge eating behavior among obese treatment-seeking adults. Peer victimization, psychosocial adjustment, and physical activity in overweight and at-risk-for-overweight youth. Internalized societal attitudes moderate the impact of weight stigma on avoidance of exercise. Unfair treatment, discrimination, and ambulatory blood pressure in black and white adolescents. Perceived weight discrimination amplifies the link between central adiposity and nondiabetic glycemic control (HbA1c). The effect of causal information on peer perceptions of children with physical problems. An attempt to reduce negative stereotyping of obesity in children by changing controllability beliefs. Obesity as a characterological stigma: the issue of responsibility and judgements of task performance. Demonstrations of implicit anti-fat bias: the impact of providing causal information and evoking empathy. Impact of perceived consensus on stereotypes about obese people: A new approach for reducing bias. However, there has also been increasing interest in the concept that exposures to environmental chemicals may be contributing factors to the remarkable changes in body composition over the past 20 years. We provide examples of known obesogens, and their general mechanisms of action, as well as emerging obesogens for which the mechanisms are less clear. The relevance and reality of the research reviewed here provides a solid foundation of knowledge from which health scientists may draw from and build upon to inform their research and decision making. Although obesogens function locally by interfering with a specific biochemical process, they can act globally to affect the entire endocrine system. Their target tissue may not always be the adipocyte, but the liver, brain, pancreas, stomach, intestines, or endocrine glands. Other end points of interest for obesogen research include glucose homeostasis, visceral versus subcutaneous fat, brown fat versus white fat, cardiovascular health, and measures of appetite and physical activity. Because the developmental period is a "plastic" phase, an organism is critically sensitive to perturbations such as alterations in hormone levels that can lead to changes in gene expression and protein levels, which persist as tissues and organs develop. Prenatal exposure to obesogenic factors can modify normal cellular and tissue development and function, especially at the level of the stem cell (discussed in section 43. Adverse perturbations in the metabolic system of the developing organism translate to a higher risk of metabolic and hormonal disorders later in life. Many disease patterns linked to poor nutrition Obesity is currently an intractable problem-nearly 90% of those who lose a significant amount of weight regain it within a year. Focusing on the fetus and/or neonate is of primary concern since, as noted in section 43. Lean individuals eat primarily to sustain fitness and tend to stop eating when they perceive they are full, even when food is bountiful. Obese people tend to eat more high-fat and high-sugar foods and continue to eat even when they are not hungry, suggesting addiction. It seems likely that at least of part of the developmental programming of disease and metabolic dysfunction is the result Environmental Chemicals and Obesity 473 of alterations in the epigenetic control of gene expression during development. The appropriate timing and extraordinary accuracy of methylation in the gametes and following fertilization makes this system particularly vulnerable to interference from environmental exposures. Chemical exposure during the pubertal period is linked with early menarche in females and delayed sexual maturation in males. Furthermore, adolescents tend to have the worst nutrition of any age group, especially with regard to sugar consumption. Using 14C labeling it has been shown that childhood and adolescent periods are the main time of adipose hyperplastic growth. Phthalate exposure is linked to increased waist circumference, incidence of diabetes, and increased fat mass. This does not necessarily mean that the indicated mechanism has been demonstrated to cause or be associated with the particular end point. Rather we wish to highlight plausible mechanisms through which the obesogens might be expected to act. These results demonstrate that obesogenic chemicals need not affect adipocytes directly, but can give an animal an increased drive to eat. Many chemicals administered during precise temporal windows during fetal development have been shown to generate phenotypes not just in the first generation, but in the second or third generation. Transgenerational effects occur when genes are epigenetically patterned to create a permanent change in the germ line. Certain diseases or gene expression changes can be found in the F3 generation (and beyond, i. Upon the discovery that they negatively affect the health of humans and other animals, use of these chemicals was banned in the United States, yet they remain persistent environmental contaminants. There have been attempts to link congener number (degree of chlorination) with the risk of obesity173; however, this research is ongoing. Although a subset of these are now banned, the majority of the population has significant blood levels. Schmidt and colleagues showed that prenatal exposure of C3H/N female mice led to increased body weight, visceral fat, and adipocyte size in F0 females and in F1 offspring. Whether obesogens exist that target, one of these mechanisms remains to be seen, but we consider this possibility quite plausible. For example, maternal smoking activates nicotinic acetylcholine receptor, which induces oxidative stress and pancreatic -cell death and reduces insulin secretion in offspring. Soy has been found in the diets of Asian populations for centuries; however, soy formula and soy milk are mostly phenomena in the United States. In particular, infant exposure levels are much higher in the United States compared to Asia. Sugars, particularly fructose, have been increasingly linked with obesity (albeit not without controversy). However, the majority of fructose is quickly metabolized in the liver215 without inducing insulin secretion. Dibutyltin and dithiocarbamate pesticides inhibit 11-hydroxysteroid dehydrogenase-2, thereby interfering with glucocorticoid breakdown and upregulating glucocorticoid levels. There are now nearly 20 chemicals shown to cause long-term weight gain and metabolic dysfunction in humans or animals and there is no systematic effort yet underway to identify obesogens or to determine whether they promote weight gain and obesity in animal models or humans. Obesogen exposure during critical periods of development can disrupt normal hormone and neuronal signaling pathways that are being established, leading to an increased vulnerability during early life. It is undoubtedly true that adults have the self-preservation instinct to entertain the idea of detoxifying themselves, avoiding chemical exposure, and increasing activity. However, emerging data from animal studies suggest that the effects of prenatal or early life obesogen exposure may be permanent and be transmitted to subsequent generations. It will be important to understand how prenatal obesogen exposure elicits transgenerational effects on fat depot 482 Handbook of Obesity 13. Developmental origins of non-communicable disease: Implications for research and public health. Altered profiles of spontaneous novelty seeking, impulsive behavior, and response to D-amphetamine in rats perinatally exposed to bisphenol A. Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. Prenatal exposure to the environmental obesogen tributyltin predisposes multipotent stem cells to become adipocytes. It will be particularly interesting to elucidate how obesogen exposure alters stem cell fate and lineage allocation in the stem cell compartment to favor adipogenesis at the expense of osteogenesis. Once outside of the womb, children and adults must further contend with the ubiquitous presence of dietary and chemical obesogens, which confound their ability to fight obesity. Determining how diet interacts with prenatal and early life obesogen exposure to influence obesity will harmonize nutritional, toxicological, endocrinological, and developmental studies that will make important contributions to our understanding of the degree to which obesogen exposure contributes to the obesity epidemic. Environmental obesogens: Organotins and endocrine disruption via nuclear receptor signaling. Endocrine disrupting chemicals and the developmental programming of adipogenesis and obesity. Role of environmental chemicals in diabetes and obesity: A national toxicology program workshop review. Endocrine-disrupting organotin compounds are potent inducers of adipogenesis in vertebrates. Epigenetic gene regulation: Linking early developmental environment to adult disease. Concentrations of urinary phthalate metabolites are associated with increased waist circumferece and insulin resistance in adult U. Serum concentrations of phthalate metabolites are related to abdominal fat distribution two years later in elderly women. Circulating levels of phthalate metabolites are associated with prevalent diabetes in the elderly. Long-term arsenic exposure and incidence of non-insulin-dependent diabetes mellitus: A cohort study in arseniasis-hyperendemic villages in Taiwan. Striking association between urinary cadmium level and albuminuria among Torres Strait Islander people with diabetes. Evaluation of status of toxic metals in biological samples of diabetes mellitus patients. Organotin compounds promote adipocyte differentiation as agonists of the peroxisome proliferator-activated receptor gamma/retinoid X receptor pathway.
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Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Quebec Cardiovascular Study bacteria yeast buy ampicillin 500 mg with visa. Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women antibiotic 50s purchase discount ampicillin on-line. Direct determination of lipoprotein particle sizes and concentrations by ion mobility analysis antibiotic hives purchase 500mg ampicillin with visa. High-density lipoprotein cholesterol as a predictor of coronary heart disease risk infection after birth cheap ampicillin 500mg free shipping. The Residual Risk Reduction Initiative: A call to action to reduce residual vascular risk in dyslipidaemic patient infection x ray purchase 500mg ampicillin amex. Assessing low levels of highdensity lipoprotein cholesterol as a risk factor in coronary heart disease: A working group report and update antibiotic resistance solutions purchase ampicillin with a mastercard. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol In Adults. Executive summary of the third report of the National Cholesterol Education Program 22. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. A strong inverse relation with the largest particles is confined to normotriglyceridemic patients. High-density lipoprotein subpopulation profile and coronary heart disease prevalence in male participants of the Framingham Offspring Study. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Triglycerides and cardiovascular disease: A scientific statement from the American Heart Association. The metabolic syndrome, its component risk factors, and progression of coronary atherosclerosis. Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey. Triglyceride- and cholesterol-rich lipoproteins have a differential effect on mild/ moderate and severe lesion progression as assessed by quantitative coronary angiography in a controlled trial of lovastatin. Impact of abdominal visceral and subcutaneous adipose tissue on cardiometabolic risk factors: the Jackson Heart Study. Effects of weight loss in overweight/obese individuals and long-term lipid outcomes-a systematic review. Low-density lipoprotein subclass patterns and lipoprotein response to a reduced-fat diet in men. A very lowfat diet is not associated with improved lipoprotein profiles in men with a predominance of large, low-density lipoproteins. Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia. Carbohydrate-induced hypertriacylglycerolemia: Historical perspective and review of biological mechanisms. Short-term consumption of a low-fat diet beneficially affects plasma lipid concentrations only when accompanied by weight loss. Changes in atherogenic dyslipidemia induced by carbohydrate restriction in men are dependent on dietary protein source. Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: Results of the OmniHeart randomized trial. Glycemic index, glycemic load, and prevalence of the metabolic syndrome in the cooper center longitudinal study. Dietary glycemic load assessed by food-frequency questionnaire in relation to plasma high-density-lipoprotein cholesterol and fasting plasma triacylglycerols in postmenopausal women. Dietary carbohydrates and cardiovascular disease risk factors in the Framingham offspring cohort. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: Metaanalyses and meta-regression models of intervention studies. Glycemic response and health-a systematic review and meta-analysis: Relations between dietary glycemic properties and health outcomes. Effects of glycemic load on metabolic risk markers in subjects at increased risk of developing metabolic syndrome. Neither raw nor retrograded resistant starch lowers fasting serum cholesterol concentrations in healthy normolipidemic subjects. Effect of highamylose starch and oat bran on metabolic variables and bowel function in subjects with hypertriglyceridemia. Effect of high-amylose starch on carbohydrate digestive capability and lipogenesis in epididymal adipose tissue and liver of rats. Niacin and fibrates in atherogenic dyslipidemia: Pharmacotherapy to reduce cardiovascular risk. Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: A systematic review and meta-analysis. Statins but not fibrates improve the atherogenic to anti-atherogenic lipoprotein particle ratio: A randomized crossover study. Fenofibrate therapy ameliorates fasting and postprandial lipoproteinemia, oxidative stress, and the inflammatory response in subjects with hypertriglyceridemia and the metabolic syndrome. Relationship between changes in insulin sensitivity and associated cardiovascular disease risk factors in thiazolidinedione-treated, insulin-resistant, nondiabetic individuals: Pioglitazone versus rosiglitazone. Peroxisome proliferator-activated receptor-gamma activation with pioglitazone improves endothelium-dependent dilation in nondiabetic patients with major cardiovascular risk factors. Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome. The major drivers of the obesity pandemic have been changes in the global food system resulting in more processed and energy-rich food that has generated an obesogenic environment. This has resulted in wide variation in the prevalence of obesity across populations, especially in adults. The obesity epidemic seems to have begun in the 1970s and 1980s in most high-income countries, spreading later on to many low-income countries. Obesity is an established risk factor for type 2 diabetes, cardiovascular disease and cancers, and nonmetabolic complications. Most patients with type 2 diabetes are obese, and visceral obesity in particular is the most important predisposing factor for the development of type 2 diabetes. However, not all obese people develop diabetes, and they typically have significantly less abnormal cardiovascular risk factor levels than those who convert to diabetes. Thus, metabolically healthy obese individuals have the ability to store free fatty acids in adipose tissue. In this chapter, we discuss the parallel pandemics of obesity and type 2 diabetes, especially from the point of view of metabolically healthy/ unhealthy obesity, which explains why a subgroup of obese people develop type 2 diabetes while others do not. Metabolically unhealthy obese individuals are characterized by insulin resistance, ectopic fat accumulation. In addition, metabolically unhealthy obese people often suffer from coexistent dyslipidemia and hypertension (Figure 49. By 2030, this number is expected to be 552 million,7 largely attributable to the increase in the incidence of type 2 diabetes. The number of people with type 2 diabetes is increasing in every country, and 80% of people with diabetes now live in low- and middle-income countries. However, not all countries with a high prevalence of diabetes have a high prevalence of obesity (such as in Southeast Asia). In contrast, in some regions with a high prevalence of obesity, the rates of diabetes are lower than one might expect. People with type 2 diabetes as well as those with prediabetes and undiagnosed type 2 diabetes are typically obese and have a high risk of cardiovascular complications, including coronary artery disease, stroke, and peripheral vascular disease. In the prediabetic state, hyperinsulinemia compensates for impaired insulin action, but for type 2 diabetes to develop, a -cell dysfunction causing impaired insulin secretion is required. Type 2 diabetes is defined by the degree of hyperglycemia Obesity and Type 2 Diabetes 541 <10. Predisposition to insulin resistance in obesity relates to adipocyte lipid turnover, deposition of fat, and adipocyte number and mass, as well as the endocrine and inflammatory properties of adipose tissue, as discussed later in Sections 49. In obese individuals, triglyceride turnover rate, determined by lipolysis followed by oxidation, is decreased, and the amount of triglycerides stored over time is increased. Adipocytes, which are derived from mesenchymal stem cells through differentiation of preadipocytes, can vary in size or number. The presence of enlarged adipocytes with greater lipid content correlates more strongly with insulin resistance than any other measure of adiposity. The recent significant advances in the identification of common genetic variants contributing to disease susceptibility have shed light on the genetic basis of both obesity and type 2 diabetes. Fifteen distinct loci affecting fat distribution have been identified by genome-wide association analyses. However, they included heterogeneous cohorts of overweight and obese individuals and did not differentiate between metabolically healthy and unhealthy individuals. The difference between healthy and unhealthy obese people in their metabolic response to lifestyle intervention is a key issue from the point of view of resources and choice of treatment. Lifestyle intervention improved insulin sensitivity significantly in the insulin-resistant group but not in the healthy obese group. However, insulin sensitivity did not improve enough in the insulin-resistant group to provide adequate protection from type 2 diabetes. Both lifestyle intervention and pharmacological treatment may be required to adequately protect metabolically susceptible individuals from developing type 2 diabetes. The use of insulin treatment and high levels of hemoglobin A1c in diabetes with a long duration were negative predictors of diabetes remission. Insulin sensitivity improved in both groups, but significantly more in the insulin-resistant group. Taken together, results from lifestyle intervention and bariatric surgery studies strongly suggest that obesity-associated insulin resistance is reversible by weight loss, at least in part. In most studies, metabolically unhealthy and insulin-resistant obese individuals have shown greater metabolic improvement in response to weight loss than metabolically healthy obese individuals. Lifestyle intervention trials and bariatric surgery offer compelling evidence for the reversibility of abnormal glucose tolerance by weight loss. Indeed, even genetic predisposition to type 2 diabetes can be overcome by favorable changes in lifestyle. Metabolically unhealthy and insulin-resistant patients have in most lifestyle intervention studies shown a greater improvement in insulin sensitivity than metabolically healthy obese individuals. Studies evaluating pathophysiological mechanisms behind metabolically unhealthy obesity and insulin resistance are likely to provide further insights into the complex link between obesity and type 2 diabetes. The leveling off of the obesity epidemic since the year 1999-a review of evidence and perspectives. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in the U. Cardiovascular disease in type 2 diabetes: Challenge for treatment and prevention. Type2 diabetes across generations: From pathophysiology to prevention and management. Subcutaneous and visceral adipose tissue: Their relation to the metabolic syndrome. From the triumvirate to the ominuous octet: A new paradigm for type 2 diabetes mellitus. Is the diminished incretin effect in type 2 diabetes just an epi-phenomenon of impaired cell function Obesity and the development of type 2 diabetes: the effects of fatty tissue inflammation. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type 2 diabes mellitus. Obesity and type 2 diabetes: What can be unified and what needs to be individualized Distribution and development of brown adipocytes in the murine and human adipose organ. Regional differences in cellular mechanisms of adipose tissue gain with overfeeding. Association of lipidome remodeling in the adipocyte membrane with acquired obesity in humans.
The transformants are plated on media containing the -galactosidase substrate Xgal antibiotics for dogs home remedy order ampicillin 250mg without a prescription. If the lacZ gene remains intact after digestion and ligation virus ny discount ampicillin 250mg visa, it will give rise to a blue colony antimicrobial qualities buy ampicillin 250 mg fast delivery. If any degradation of the cut ends occurred antimicrobial use generic 250mg ampicillin visa, then a white colony will be produced (Box 3 antibiotics used for urinary tract infections generic ampicillin 250mg overnight delivery. The third utilizes the enzyme terminal deoxynucleotidyltransferase to synthesize homopolymeric 3 single-stranded tails at the ends of fragments infection genetics and evolution best order for ampicillin. When termini created by a restriction endonuclease that creates cohesive ends associate, the joint has nicks a few base pairs apart in opposite strands. Note that the two digests give an identical banding pattern upon agarose gel electrophoresis. The activity of the enzyme b-galactosidase is easily monitored by including in the growth medium the chromogenic substrate 5-bromo4-chloro-3-indolyl-b-D-galactoside (Xgal). If a plasmid carrying the N-terminal fragment of the lacZ gene encompassing the missing region is introduced into the M15 mutant, then b-galactosidase is produced, as demonstrated by the production of a blue color on medium containing Xgal. While a gene of this length is easily manipulated in vitro, there are practical disadvantages to using the whole gene. As will be seen later, it is preferable to keep cloning vectors and their inserts as small as possible. The phenomenon of a-complementation allows genetic engineers to take advantage of the lac system without having to have the entire Z gene on the vector. The ligation reaction can be performed so as to favor the formation of recombinants. One nick at each join remains unligated, but, after transformation of host bacteria, cellular repair mechanisms reconstitute the intact duplex. Blunt ligation is most usefully applied to joining blunt-ended fragments via linker molecules; in an early example of this, Scheller et al. Another solution is to methylate internal restriction sites with the appropriate modification methylase. Alternatively, a general solution to the problem is provided by chemically synthesized adaptor molecules which have a preformed cohesive end (Wu et al. The terminal transferase reactions have been characterized in detail with regard to their use in gene manipulation (Deng & Wu 1981, Michelson & Orkin 1982). The recombinants were then transfected into susceptible mammalian cells (see Chapter 12). Because the extra sequence can be chosen at the will of the experimenter, great flexibility is available here. A common application of this principle is the incorporation of restriction sites at each end of the amplified product. A linearized vector with single 3 T extensions is activated with the topoisomerase. In addition, the high substrate specificity of the enzyme means that there is a low rate of formation of vectors without inserts. Two primers have sequences designed to hybridize at the ends of the target region. If they are on different molecules, and one of the molecules is circular, then an insertion event will occur. The best example of this is the chromosomal insertion of the genome of bacteriophage l during the process of lysogeny. With some recombinases, like Cre and Flp, the sites where recombination takes place. Since recombination does not involve the gain or loss of nucleotides it is said to be conservative. The site consists of three 13 bp symmetry elements (shown by arrows), one of which (a) is in a different orientation to the other two (b and c). The "a" and "b" elements are separated by an 8-bp asymmetric sequence across which recombination takes place. The attP and attB sites are mostly dissimilar and have only the central 15 bases in common (inset). In the variation described by Sadowski (2003), the Flp recombinase is used and this generates recombinants in which the flanking sites remain unchanged. There are two major applications of cloning with recombinases: recloning and recombineering. A series of specialist vectors (the Gateway vectors) have been designed for this purpose and these are described on p. It is difficult to manipulate in vitro vectors containing such large inserts and usually it is preferable to do the manipulations in vivo. Other applications of recombinases are described in the review of Schweizer (2003). Input plasmid 1 Input plasmid 2 Recombinase Output plasmid 1 Output plasmid 2. An excellent review of host-controlled restriction and modification which provides an historical perspective on the development of restriction enzymes. Two reviews that provide additional detail to the material covered in this chapter. This website details everything that you need to know before using any of these enzymes. When isolated from cells, covalently closed circles often have a deficiency of turns in the double helix, such that they have a supercoiled configuration. If excess ethidium bromide is added, the plasmid will rewind in the opposite direction. To prevent nuclease digestion, the ends of linear plasmids need to be protected, and two general mechanisms have evolved. For more details of linear plasmids the reader should consult Hinnebusch and Tilly (1993). Some of the phenotypes which these plasmids confer on their host cells are listed in Table 4. Plasmids to which phenotypic traits have not yet been ascribed are called cryptic plasmids. Plasmids can also be categorized on the basis of their being maintained as multiple copies per cell (relaxed plasmids) or as a limited number of copies per cell (stringent plasmids). Generally, conjugative plasmids are of relatively high molecular weight and are present as one to three copies per chromosome, whereas non-conjugative plasmids the reader should not be confused by the terms relaxed circle and relaxed plasmid. Under the conditions of electrophoresis employed here, the linear form migrates just ahead of the open circular form. As the amount of intercalated ethidium bromide increases, the double helix untwists, with the result that the supercoiling decreases until the relaxed form of the circular molecule is produced. Further intercalation introduces excess turns in the double helix, resulting in supercoiling in the opposite sense (note the direction of coiling at B and D). Antibiotic resistance Antibiotic production Degradation of aromatic compounds Hemolysin production Sugar fermentation Enterotoxin production Heavy-metal resistance Bacteriocin production Induction of plant tumors Hydrogen sulfide production Host-controled restriction and modification Basic biology of plasmid and phage vectors 57 Table 4. Those replication proteins that are plasmid-encoded are located very close to the ori (origin of replication) sequences at which they act. Other parts of the plasmid can be deleted and foreign sequences can be added to the plasmid and replication will still occur. This feature of plasmids has greatly simplified the construction of versatile cloning vectors. Plasmids whose ori region is derived from plasmid Col E1 have a restricted host range: they only replicate in enteric bacteria, such as E. Many of the plasmids isolated from Staphylococcus aureus also have a broad host range and can replicate in many other Gram-positive bacteria. Plasmids with a broad host range encode most, if not all, of the proteins required for replication. They must also be able to express these genes and thus their promoters and ribosome binding sites must have evolved such that they can be recognized in a diversity of bacterial families. The number of copies of a plasmid in a cell varies between plasmids and is determined by the regulatory mechanisms controlling replication the copy number of a plasmid is determined by regulating the initiation of plasmid replication. First, the RepA protein represses its own synthesis by binding to its own promoter region and blocking transcription of its own gene (Ingmer & Cohen 1993). After cell division, the copy number and concentration of RepA will drop and replication will be initiated. Mutations in the RepA protein can lead to increased copy number (Ingmer & Cohen 1993, Cereghino et al. Secondly, the RepA protein can link two plasmids together, by binding to their iteron sequences, thereby preventing them from initiating replication. The location of the partitioning site par and the binding sites for the host protein DnaA are also shown. These multimeric forms are not seen with Col E1, which has a natural method of resolving multimers back to monomers. If the cer sequence occurs more than once in a plasmid, as in a multimer, the host-cell Xer protein promotes recombination, thereby regenerating monomers (Summers & Sherratt 1984, Guhathakurta et al. Plasmids with similar replication and partitioning systems cannot be maintained in the same cell Plasmid incompatibility is the inability of two different plasmids to coexist in the same cell in the absence of selection pressure. Groups of plasmids which are mutually incompatible are considered to belong to the same incompatibility (Inc) group. Plasmids will be incompatible if they have the same mechanism of replication control. Alternatively, they will be incompatible if they share the same par region (Austin & Nordstrom 1990, Firsheim & Kim 1997). Naturally occurring plasmids are stably maintained because they contain a partitioning function, par, which ensures that they are stably maintained at each cell division. Such par regions are essential for stability of low-copy-number plasmids (for review, see Bingle & Thomas 2001). The highercopy-number plasmid Col E1 also contains a par region but this is deleted in many Col E1-derived cloning vectors. Plasmid instability may also arise due to the formation of multimeric forms of a plasmid. The mechanism that controls the copy number of a plasmid ensures a fixed number of plasmid origins per bacterium. The first of these is the "classical" method and is due to Vinograd (Radloff et al. This method involves isopycnic centrifugation of cleared lysates in a solution of CsCl containing ethidium bromide (EtBr). The precipitate can be removed by centrifugation and the plasmid concentrated by ethanol precipitation. All of them take advantage of the benefits of alkaline lysis and have as their starting point the cleared lysate. The first of these is the actual copy number inside the cells at the time of harvest. The copynumber control systems described earlier are not the only factors affecting yield. The copy number is also affected by the growth medium, the stage of growth and the genotype of the host cell (Nugent et al. The second and most important factor is the care taken in making the cleared lysate. Unfortunately, the commercially available kits have not removed the vagaries of this procedure. Finally, the presence in the host Basic biology of plasmid and phage vectors 61 cell of a wild-type endA gene can affect the recovery of plasmid. Strains bearing endA mutations have no obvious phenotype other than improved stability and yield of plasmid obtained from them. Although most cloning vehicles are of low molecular weight (see next section), it is sometimes necessary to use the much larger conjugative plasmids. Although these high-molecular-weight plasmids can be isolated by the methods just described, the yields are often very low. Either there is inefficient release of the plasmids from the cells as a consequence of their size or there is physical destruction caused by shear forces during the various manipulative steps. A number of alternative procedures have been described (Gowland & Hardmann 1986), many of which are a variation on that of Eckhardt (1978). Bacteria are suspended in a mixture of Ficoll and lysozyme and this results in a weakening of the cell walls. The samples are then placed in the slots of an agarose gel, where the cells are lysed by the addition of detergent. The use of agarose, which melts at low temperature, facilitates extraction of the plasmid from the gel.
In 2008 antimicrobial news order generic ampicillin line, we examined the relationship between active transportation (defined as the percentage of trips taken by walking antibiotics and pregnancy buy generic ampicillin canada, bicycling virus movie discount 250 mg ampicillin fast delivery, and public transit) and obesity rates in 15 countries in Europe bacteria brutal order ampicillin 500 mg overnight delivery, North America bacteria reproduce by binary fission cheap 500mg ampicillin overnight delivery, and Australia antibiotics and mirena ampicillin 500 mg lowest price. The results showed that countries with the highest levels of active transportation tended to have the lowest obesity rates (Figure 38. Although the daily impact may seem small, over the course of a year it amounts to a substantial oxidation of body fuel. The results are consistent with the view that variations in the use of active transportation contribute to international differences in obesity rates. Data were obtained from national surveys of travel behavior and health indicators conducted from 1994 to 2006. They examined aggregate, cross-sectional data and found statistically significant positive relationships between active commuting and overall levels of physical activity. In addition, there were statistically significant negative relationships between active travel and rates of obesity/diabetes. This study provided evidence of the public health benefits of active travel, and the authors concluded that policies on transport, land use, and urban development should be made to encourage walking and bicycling. One of the limitations of ecological studies such as the aforementioned ones (which rely on aggregate, rather than individual-level, data) is that they can be subject to "ecological fallacy. Although these types of studies are easier to perform and are valuable because they provide a first look at a problem, they should be confirmed by studies using individual-level data. Of 30 studies assessing active transport and body weight, 13 reported associations in the expected direction (more active transport associated with lower body weight) for all or most of the variables examined, 12 found some associations, 2 observed some associations in the expected direction and some in the opposite direction, and 3 reported no associations. The authors concluded that, on the basis of cross-sectional studies in adults, active transport is associated with higher total physical activity levels and lower body weights in adults. The relationship between active commuting to school and physical activity and body weight has also been examined in children, with quite different results than those found in adults. Most studies that looked at physical activity found a positive association between active commuting and overall levels of physical activity. However, only 3 of 18 studies examining body weight found consistent results in the expected direction, suggesting there might be no association between active commuting and reduced weight in children. The presence of confounding variables that were not adequately controlled for could have contributed to this finding. Studies have examined the relationship between active transportation or active commuting. Of 15 studies assessing active transport and overall physical activity levels, 5 found associations in the expected direction (more active transport linked to more physical activity) for all or 38. In the 1980s few households in China owned motor vehicles, but 14% of Chinese households acquired a motor vehicle between 1989 and 1997. A subsequent study also used longitudinal data from the China Health and Nutrition Examination Survey. The study cohort was divided into two groups: those who used light rail to commute to work and those who did not. In summary, the scientific evidence suggests that regular use of active transportation modes is associated with a lower body weight in adults. Furthermore, the results of longitudinal studies indicate that active commuting is helpful in maintaining normal body weight. Thus, some researchers and practitioners have turned to policy approaches, believing that they can be more effective for increasing physical activity. Policies consist of laws, regulations, and rules that can determine changes in physical, economic, and social environments. Furthermore, it allowed states to opt out, or transfer funds from bike and pedestrian programs to other uses like environmental mitigation. A bicycle advocacy organization projects that these changes will lead to a substantial decline in pedestrian and bicycle projects. All states and municipalities have their own policies that can impact transportation infrastructure, programs, and enforcement. In 2011 car ownership in the United States was 808 vehicles per 1000 residents,57 but in European countries it ranged from 450 to 690 vehicles per 1000 residents. These federal agencies set and enforce safety standards for the design, manufacture, and operation of vehicles; oversee building of highways and railroads; and allocate money to cities for the improvement of public transit systems. In the United States, the federal interstate highway system was established in 1956, during the Eisenhower administration, after many industry and civic groups joined forces to lobby for improved highways. The Federal Highway Administration provides grants to states through a funding and authorization bill that governs surface transportation spending. The decision to allocate a large portion of transportation funds to interstate and state highways and bridges has resulted in a well-developed network of highways throughout the country that assists long-distance driving, but it has also contributed to sprawl. In contrast, only about 1% to 2% of all transportation funding is allocated to pedestrian/ bicycle program improvements. In contrast to the United States, many European nations have federal policies that promote walking, cycling, and public transit use and actively discourage the use of personal automobiles. It awards grants to municipalities for the construction of local roads, sidewalks, bike lanes, and greenways. One example of a local policy that can have a tremendous impact on the built environment is an urban growth boundary. As a result, developers must build within the urban growth boundary, which favors "infill" rather than everexpanding sprawl. Local zoning and sidewalk ordinances also influence the walkability of communities. In some places, transportation engineers follow the status quo and use a reference called the American Association of State Highway and Transportation Officials green book. The green book focuses on increasing vehicle throughput, often resulting in the construction of wider, faster roads. Many cities have adopted complete street policies, which require transportation infrastructure for a variety of modes and embed that requirement into a policy such as an executive order or design guidelines. Such policies can have a great impact on making the roadways accessible to all types of users, not just car drivers. There may be a separate pedestrian and bicycle master plan, which lays out groundwork for improvements to active transportation infrastructure, or it may be contained within the larger transportation plan. These plans vary widely with regard to plan quality elements, including public participation and planning processes, plan goals and objectives, analysis of current trends and conditions, policies and proposals, and implementation. Since people normally walk or cycle to the transit stops, they acquire additional physical activity by using the subways and trains. These systems may be built with a combination of federal funds and local matching funds. Bus transit systems are found in 900 cities in the United States, and they also contribute to an increase in population physical activity levels. This provides them with opportunities to be physically active on a regular basis and decreases the likelihood of weight gain. Health and Community Design: the Impact of the Built Environment on Physical Activity. Infrastructure, programs and policies to increase bicycling: An international review. Focus on Personal Travel (including the Report of the National Travel Survey 2002/2003): Great Britain National Travel Survey Unit, Statistics Travel, 2005. Urban transport trends and policies in China and India: Impacts of rapid economic growth. Promoting safe walking and cycling to improve public health: Lessons from the Netherlands and Germany. Physical activity and coronary heart disease in women: Is "no pain, no gain" passe By making it easier for people to commute to work and run errands using green modes of transport, governments can encourage the populace to obtain more physical activity. The notion that active transportation is helpful in preventing obesity is consistent with the scientific evidence that daily bouts of physical activity, over long periods of time, can have a large impact on the regulation of body weight. A prospective study of walking as compared with vigorous exercise in the prevention of coronary heart disease in women. Influence of exercise, walking, cycling, and overall nonexercise physical activity on mortality in Chinese women. Domains of physical activity and all-cause mortality: Systematic review and dose-response meta-analysis of cohort studies. Trend and prevalence estimates based on the 2008 Physical Activity Guidelines for Americans. Physical activity epidemiology: Concepts, methods, and applications to exercise science. Physical activity patterns among adults in Georgia: Results from the 1990 Behavioral Risk Factor Surveillance System. Obesity relationships with community design, physical activity, and time spent in cars. Walking and cycling to health: A comparative analysis of city, state, and international data. Active transport, physical activity, and body weight in adults: A systematic review. The road to obesity or the path to prevention: Motorized transportation and obesity in China. Motorized transportation, social status, and adiposity: the China health and nutrition survey. Changes in weight, waist circumference and compensatory responses with different doses of exercise among sedentary, overweight postmenopausal women. Association of State and Territorial Directors of Health Promotion and Public Health Education. Safe, Accountable, Flexible, Efficient Transportation Equity Act: A Legacy for Users. Study on Vehicle Taxation in Member States of the European Union, Final Report; January, 2002. Planning for pedestrians and bicyclists: Results from a statewide municipal survey. Physical activity in the prevention of obesity: Current evidence and research issues. The Pima share identical genetics and ancestral traditions, yet the two communities occupy land in very different countries with very different cultures. It is no surprise that differences have developed, including language, culture, and food, that set the two subpopulations apart from each other. What may be surprising is that the Arizona Pima have a higher incidence of obesity as well as type 2 diabetes rates that are five times their Mexican Pima relatives. Can the physical environment have this much of a direct impact on weight and associated diseases or are other sociocultural and economic factors to blame There is a long-running debate in the field of urban planning about the degree to which the physical environment determines human behavior. One view, environmental determinism, ascribes great importance to the physical environment as a shaper of behavior. The counterview is that social and economic factors are the main or even exclusive determinants of behavior. So far, this debate is, at least empirically, decidedly undecided and wide open to personal interpretation. Nearly all evidence of association between the built environment and obesity is based on cross-sectional data, which provide few clues as to cause and effect. From the array of results, one can just as easily argue that physically active and physically fit people choose to live in pedestrian-friendly environments (self-selection) as that those environments cause people to be more physically active and hence healthier (environmental determinism). It is often the case with social science inquiry, causal direction is difficult to establish. In this chapter, we review what is known about the built environment and its relationship to physical activity and obesity. The built environment includes everything from metropolitan land-use patterns and urban transportation systems to individual buildings and the spaces around them. Land patterns, as part of the built environment, come in varying degrees of two basic forms. Examples of compact development, the opposite of sprawl, are so few and far between that they seem almost quaint these days. For every New York metropolitan area, there are dozens of areas like Atlanta and Detroit. For every Manhattan, 437 438 Handbook of Obesity there are hundreds of Walton and Lapeer counties (counties located on the periphery of the Atlanta and Detroit metropolitan areas). An early definition emphasized poor accessibility and lack of functional open space as two primary indicators of sprawling development. In sprawl, poor accessibility of land uses and limited connectivity may leave residents with no alternative to automobile travel.