Obesity resistance

Bachman ES, Dhillon H, Zhang CY, et al. P-AR Signaling required for diet-induced thermogenesis and obesity resistance. Science 2002 297 843-845. 

S.J. Smith, S. Cases, and D.R. Jensen, et al.. Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat, Nat. Gen., 2000, 25,... 

Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-IB gene. Science 283 1544-1548... 

Chen, C.S., Bench, E.M., Allerton, T.D., Schreiber, A.L., Arceneaux, K.P. 3 Primeaux, S.D. Preference for linoleic acid in obesity-prone and obesity-resistant rats is attenuated by the reduction of CD36 on the tongue. Am. J. Physiol Regul Integr. Comp. Physiol. 2013,305 R1346-R1355. 

Belobrajdic DP, King RA, Christophersen CT, Bird AR. Dietary resistant starch dose-dependently reduces adiposity in obesity-prone and obesity-resistant male rats. Nutr Metabol. 2012 9(1) 93. 

Leptin has proved to be an efficient treatment for the rare form of obesity associated with leptin deficiency. By contrast, the results of the fust clinical trial with human leptin in obese patients (without leptin deficiency) were less promising. This may be explained by leptin resistance in a high proportion of these patients. However, the mechanisms involved in the development of leptin resistance could become new drug targets. 

Leptin is a cytokine produced and secreted by adipose tissue in proportion to the body fat content [3]. Mice and humans lacking leptin or its receptor develop a severe hyperphagia and a dramatic degree of obesity which is considerably more pronounced than that of the NDRKO mouse. Thus, leptin is the key adiposity signal in rodents and humans. Leptin secretion appears to reflect the metabolic status of the adipocyte rather than the sheer size of triglyceride deposits, and leptin levels may transiently be dissociated from total body fat. Nonetheless, over the course of a day with unrestricted food supply, plasma leptin levels reliably reflect the amount of total body fat. Local administration of leptin into the brain results in reduced food intake. The vast majority of patients with obesity have elevated serum levels of leptin. Thus, it is believed that the polygenic obesity is due to leptin resistance rather than to inadequate leptin secretion, or to a reduced blood/brain transport of the cytokine. 

Leptin has been shown to markedly reduce appetite and weight in the extremely rare individuals who lack leptin. In contrast, in the first clinical study of patients with polygenic obesity and elevated leptin levels, weight loss was variable and relatively small. This disappointing result may be explained by the leptin resistance consistently observed in obese humans and rodents. However, it cannot be excluded that a small... 

Thiazolidinediones (synonyms glitazones, insulin sensitizers rosiglitazone, pioglitazone) are a novel class of oral antidiabetic drugs that activate the transcription factor peroxisome proliferator-activated receptor (PPARy). Thiazolidinediones ameliorate insulin resistance in obese animal models and in individuals... 

Insulin resistance occurs when the normal response to a given amount of insulin is reduced. Resistance of liver to the effects of insulin results in inadequate suppression of hepatic glucose production insulin resistance of skeletal muscle reduces the amount of glucose taken out of the circulation into skeletal muscle for storage and insulin resistance of adipose tissue results in impaired suppression of lipolysis and increased levels of free fatty acids. Therefore, insulin resistance is associated with a cluster of metabolic abnormalities including elevated blood glucose levels, abnormal blood lipid profile (dyslipidemia), hypertension, and increased expression of inflammatory markers (inflammation). Insulin resistance and this cluster of metabolic abnormalities is strongly associated with obesity, predominantly abdominal (visceral) obesity, and physical inactivity and increased risk for type 2 diabetes, cardiovascular and renal disease, as well as some forms of cancer. In addition to obesity, other situations in which insulin resistance occurs includes... 

Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Qin Invest 116 1494-1505 Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410 988-994... 

Lifestyle changes should address other risk factors for cardiovascular disease including obesity, physical inactivity, insulin resistance, dyslipidemia, smoking cessation, and others. 

Patients with metabolic syndrome are twice as likely to develop type 2 diabetes and four times more likely to develop CHD.3,11 These individuals are usually insulin resistant, obese, have hypertension, are in a prothrombotic state, and have atherogenic dyslipidemia characterized by low HDL cholesterol and elevated triglycerides, and an increased proportion of their LDL particles are small and dense.3... 

Poor sleep architecture and fragmented sleep secondary to OSA can cause excessive daytime sleepiness (EDS) and neu-rocognitive deficits. These sequelae can affect quality of life and work performance and may be linked to occupational and motor vehicle accidents. OSA is also associated with systemic disease such as hypertension, heart failure, and stroke.21-23 OSA is likely an independent risk factor for the development of hypertension.24 Further, when hypertension is present, it is often resistant to antihypertensive therapy. Fatal and non-fatal cardiovascular events are two- to threefold higher in male patients with severe OSA.25 OSA is associated with or aggravates biomarkers for cardiovascular disease, including C-reactive protein and leptin.26,27 Patients with sleep apnea often are obese and maybe predisposed to weight gain. Hence, obesity may further contribute to cardiovascular disease in this patient population. 

Insulin resistance has been associated with a number of other cardiovascular risks, including abdominal obesity, hypertension, dyslipidemia, hypercoagulation, and hyperinsulinemia. The clustering of these risk factors has been termed metabolic syndrome. It is estimated that 50% of the United States population older than 60 years of age have metabolic syndrome. The most widely used criteria to define metabolic syndrome were established by the National Cholesterol Education Program Adult Treatment Panel III Guidelines (summarized in Table 40-2). 

Differential diagnoses include diabetes mellitus and metabolic syndrome because patients with these conditions share several similar characteristics with Cushing s syndrome patients (e.g., obesity, hypertension, hyperlipidemia, hyperglycemia, and insulin resistance). In women, the presentations of hirsutism, menstrual abnormalities, and insulin resistance are similar to those of polycystic ovary syndrome. Cushing s syndrome can be differentiated from these conditions by identifying the classic signs and symptoms of truncal obesity, "moon faces" with facial plethora, a "buffalo hump" and supraclavicular fat pads, red-purple skin striae, and proximal muscle weakness. 

Acanthosis nigricans A skin condition characterized by dark, thickened velvety patches, especially in the folds of skin in the armpits, groin, and back of the neck that is often associated with insulin resistance. Also may be associated with internal malignancy, endocrine disorders, and obesity. 

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