The extreme obesity of the obese (ob/ob) mouse is attributable to mutations in the gene encoding leptin, an adipocyte-specific secreted protein which has profound effects on appetite and energy expenditure. We know of no equivalent evidence regarding leptin's role in the control of fat mass in humans. We have examined two severely obese children who are members of the same highly consanguineous pedigree. Their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found. The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans.

The presence of a diabetic cardiomyopathy, independent of hypertension and coronary artery disease, is still controversial. This systematic review seeks to evaluate the evidence for the existence of this condition, to clarify the possible mechanisms responsible, and to consider possible therapeutic implications. The existence of a diabetic cardiomyopathy is supported by epidemiological findings showing the association of diabetes with heart failure; clinical studies confirming the association of diabetes with left ventricular dysfunction independent of hypertension, coronary artery disease, and other heart disease; and experimental evidence of myocardial structural and functional changes. The most important mechanisms of diabetic cardiomyopathy are metabolic disturbances (depletion of glucose transporter 4, increased free fatty acids, carnitine deficiency, changes in calcium homeostasis), myocardial fibrosis (association with increases in angiotensin II, IGF-I, and inflammatory cytokines), small vessel disease (microangiopathy, impaired coronary flow reserve, and endothelial dysfunction), cardiac autonomic neuropathy (denervation and alterations in myocardial catecholamine levels), and insulin resistance (hyperinsulinemia and reduced insulin sensitivity). This review presents evidence that diabetes is associated with a cardiomyopathy, independent of comorbid conditions, and that metabolic disturbances, myocardial fibrosis, small vessel disease, cardiac autonomic neuropathy, and insulin resistance may all contribute to the development of diabetic heart disease.

Activation of peroxisome proliferator-activated receptor (PPAR) gamma, a nuclear receptor highly expressed in adipocytes, induces the differentiation of murine preadipocyte cell lines. Recently, thiazolidinediones (TZDs), a novel class of insulin-sensitizing compounds effective in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) have been shown to bind to PPARgamma with high affinity. We have examined the effects of these compounds on the differentiation of human preadipocytes derived from subcutaneous (SC) and omental (Om) fat. Assessed by lipid accumulation, glycerol 3-phosphate dehydrogenase activity, and mRNA levels, subcultured preadipocytes isolated from either SC or Om depots did not differentiate in defined serum-free medium. Addition of TZDs (BRL49653 or troglitazone) or 15-deoxyDelta12,14prostaglandin J2 (a natural PPARgamma ligand) enhanced markedly the differentiation of preadipocytes from SC sites, assessed by all three criteria. The rank order of potency of these agents in inducing differentiation matched their ability to activate transcription via human PPARgamma. In contrast, preadipocytes from Om sites in the same individuals were refractory to TZDs, although PPARgamma was expressed at similar levels in both depots. The mechanism of this depot-specific TZD response is unknown. However, given the association between Om adiposity and NIDDM, the site-specific responsiveness of human preadipocytes to TZDs may be involved in the beneficial effects of these compounds on in vivo insulin sensitivity.

Survival of multicellular organisms depends on their ability to fight infection, metabolize nutrients, and store energy for times of need. Unsurprisingly, therefore, immunoregulatory and metabolic mechanisms interact in human conditions such as obesity. Both infiltrating immunoinflammatory cells and adipocytes play critical roles in the modulation of metabolic homeostasis, so it is important to understand factors that regulate both adipocyte and immune cell function. A currently favored paradigm for obesity-associated metabolic dysfunction is that chronic macronutrient and/or lipid overload (associated with adiposity) induces cellular stress that initiates and perpetuates an inflammatory cycle and pathophysiological signaling of immunoinflammatory cells and adipocytes. Many lipid mediators exert their biological effects by binding to cognate receptors, such as G-protein-coupled receptors and Toll-like receptors. This process is tightly regulated under normal physiological conditions, and any disruption can initiate disease processes. Observations that cellular lipid loading (associated with adiposity) initiates inflammatory events has encouraged studies on the role of lipid mediators. In this review, we speculate that lipid mediators act on important immune receptors to induce low-grade tissue inflammation, which leads to adipocyte and metabolic dysfunction.

In type 2 diabetes, hyperglycemia is present when an increased demand for insulin, typically due to insulin resistance, is not met as a result of progressive pancreatic beta cell dysfunction. This defect in beta cell activity is typically characterized by impaired insulin biosynthesis and secretion, usually accompanied by oxidative and endoplasmic reticulum (ER) stress. We demonstrate that multiple inflammatory cytokines elevated in diabetic pancreatic islets induce beta cell oxidative and ER stress, with interleukin-23 (IL-23), IL-24 and IL-33 being the most potent. Conversely, we show that islet-endogenous and exogenous IL-22, by regulating oxidative stress pathways, suppresses oxidative and ER stress caused by cytokines or glucolipotoxicity in mouse and human beta cells. In obese mice, antibody neutralization of IL-23 or IL-24 partially reduced beta cell ER stress and improved glucose tolerance, whereas IL-22 administration modulated oxidative stress regulatory genes in islets, suppressed ER stress and inflammation, promoted secretion of high-quality efficacious insulin and fully restored glucose homeostasis followed by restitution of insulin sensitivity. Thus, therapeutic manipulation of immune regulators of beta cell stress reverses the hyperglycemia central to diabetes pathology.

Background and aim: Obesity is a risk factor for progression of fibrosis in chronic liver diseases such as non-alcoholic fatty liver disease and hepatitis C. The aim of this study was to investigate the longer term effect of weight loss on liver biochemistry, serum insulin levels, and quality of life in overweight patients with liver disease and the effect of subsequent weight maintenance or regain. Patients: Thirty one patients completed a 15 month diet and exercise intervention. Results: On completion of the intervention, 21 patients (68%) had achieved and maintained weight loss with a mean reduction of 9.4 (4.0)% body weight. Improvements in serum alanine aminotransferase (ALT) levels were correlated with the amount of weight loss (r = 0.35, p = 0.04). In patients who maintained weight loss, mean ALT levels at 15 months remained significantly lower than values at enrolment (p = 0.004), while in regainers (n = 10), mean ALT levels at 15 months were no different to values at enrolment (p = 0.79). Improvements in fasting serum insulin levels were also correlated with weight loss (r = 0.46, p = 0.04), and subsequent weight maintenance sustained this improvement. Quality of life was significantly improved after weight loss. Weight maintainers sustained recommended levels of physical activity and had higher fasting insulin levels (p = 0.03) at enrolment than weight regainers. Conclusion: In summary, these findings demonstrate that maintenance of weight loss and exercise in overweight patients with liver disease results in a sustained improvement in liver enzymes, serum insulin levels, and quality of life. Treatment of overweight patients should form an important component of the management of those with chronic liver disease.T he prevalence of obesity and overweight has risen at an alarming rate over the past 20 years.1 In addition to increasing the risk of the development of type 2 diabetes, hypertension, and dyslipidaemia, excess body weight also has an adverse effect on the liver. Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognised condition that is often seen in patients who are overweight or diabetic or in those with the insulin resistance syndrome.2 It encompasses a wide spectrum of liver pathology, ranging from steatosis to steatohepatitis, fibrosis, and cirrhosis. 3 In patients with NAFLD, the clinical risk factors that are associated with liver injury include elevated body mass index (BMI), visceral adiposity (increased waist circumference), presence of type 2 diabetes, and systemic hypertension. Obesity is also recognised as an independent risk factor for the progression of fibrosis in other chronic liver diseases. 6 A number of studies have now demonstrated an association between increased BMI or visceral adiposity and hepatic steatosis 7 and fibrosis 8 in patients infected with hepatitis C virus (HCV). In overweight patients with chronic HCV, we recently demonstrated an association between increasing insulin levels and increasing hepatic fibrosis, suggesting that host metabolic facto...

Eight weeks administration of resveratrol did not significantly improve any features of NAFLD, compared with placebo, but it increased hepatic stress, based on observed increases in levels of liver enzymes. Further studies are needed to determine whether agents that are purported to mimic calorie restriction, such as resveratrol, are safe and effective for complications of obesity. Clinical trials registration no: ACTRN12612001135808.

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