Cancer-associated cachexia (CAC) is a wasting syndrome characterized by systemic inflammation, body weight loss, atrophy of white adipose tissue (WAT) and skeletal muscle. Limited therapeutic options are available and the underlying mechanisms are poorly defined. Here we show that a phenotypic switch from WAT to brown fat, a phenomenon termed WAT browning, takes place in the initial stages of CAC, before skeletal muscle atrophy. WAT browning is associated with increased expression of uncoupling protein 1 (UCP1), which uncouples mitochondrial respiration toward thermogenesis instead of ATP synthesis, leading to increased lipid mobilization and energy expenditure in cachectic mice. Chronic inflammation and the cytokine interleukin-6 increase UCP1 expression in WAT, and treatments that reduce inflammation or β-adrenergic blockade reduce WAT browning and ameliorate the severity of cachexia. Importantly, UCP1 staining is observed in WAT from CAC patients. Thus, inhibition of WAT browning represents a promising approach to ameliorate cachexia in cancer patients.

Adiponectin is an adipocyte hormone that links visceral adiposity with insulin resistance and atherosclerosis. It is unique among adipocyte-derived hormones in that its circulating concentrations are inversely proportional to adiposity, and low adiponectin concentrations predict the development of type 2 diabetes and cardiovascular disease. Consequently, in the decade since its discovery, adiponectin has generated immense interest as a potential therapeutic target for the metabolic syndrome and diabetes. This review summarizes current research regarding the regulation of circulating adiponectin concentrations by physiological, pharmacological, and nutritional factors, with an emphasis on human studies. In humans, plasma adiponectin concentrations are influenced by age and gender, and are inversely proportional to visceral adiposity. In vitro studies suggest that adiponectin production may be determined primarily by adipocyte size and insulin sensitivity, with larger, insulin-resistant adipocytes producing less adiponectin. While adiponectin concentrations are unchanged after meal ingestion, they are increased by significant weight loss, such as after bariatric surgery. In addition, adiponectin production is inhibited by a number of hormones, including testosterone, prolactin, glucocorticoids and growth hormone, and by inflammation and oxidative stress in adipose tissue. Smoking decreases, while moderate alcohol consumption increases, circulating adiponectin concentrations. Dietary fatty acid composition in rodents influences adiponectin production via ligand-activated nuclear receptors (PPARs); however, current evidence in humans is equivocal. In addition to PPAR agonists (such as thiazolidinediones and fibrates), a number of pharmacological agents (angiotensin receptor type 1 blockers, ACE inhibitors, and cannabinoid receptor antagonists) used in treatment of the metabolic syndrome also increase adiponectin concentrations in humans.

Brown adipose tissue (BAT) plays a key role in energy homeostasis and thermogenesis in animals, conferring protection against diet-induced obesity and hypothermia through the action of uncoupling protein 1 (UCP1). Recent metabolic imaging studies using positron emission tomography computerized tomography (PET-CT) scanning have serendipitously revealed significant depots of BAT in the cervical-supraclavicular regions, demonstrating persistence of BAT beyond infancy. Subsequent cold-stimulated PET-CT studies and direct histological examination of adipose tissues have demonstrated that BAT is highly prevalent in adult humans. BAT activity correlates positively with increment of energy expenditure during cold exposure and negatively with age, body mass index, and fasting glycemia, suggesting regulatory links between BAT, cold-induced thermogenesis, and energy metabolism. Human BAT tissue biopsies express UCP1 and harbor inducible precursors that differentiate into UCP1-expressing adipocytes in vitro. These recent discoveries represent a metabolic renaissance for human adipose biology, overturning previous belief that BAT had no relevance in adult humans. They also have implications for the understanding of the pathogenesis and treatment of obesity and its metabolic sequelae.

Sucrose and HFCS do not have substantially different short-term endocrine/metabolic effects. In male subjects, short-term consumption of sucrose and HFCS resulted in postprandial TG responses comparable to those induced by fructose.

SUMMARY Activation of AMP-activated protein kinase (AMPK) is thought to convey many of the beneficial effects of exercise via its inhibitory effect on acetyl-CoA carboxylase 2 (ACC2) and promotion of fatty acid oxidation. Hence, AMPK and ACC have become major drug targets for weight loss and improved insulin action. However, it remains unclear if or how activation of the fatty acid oxidation pathway without a concomitant increase in energy expenditure could be beneficial. In this study we have used either pharmacological (administration of the AMPK agonist 5′ aminoimidazole-4-carboxamide-riboside (AICAR)) or genetic means (mutation of the ACC2 gene in mice) to manipulate fatty acid oxidation to determine if this is sufficient to promote leanness. Both of these strategies increased whole body fatty acid oxidation without altering energy expenditure or adiposity. We conclude that negative energy balance is a pre-requisite for weight reduction and increased fatty acid oxidation per se has little, if any, effect to reduce adiposity.

BAT is present in supraclavicular fat, regardless of PET status. BAT is highly prevalent in adult humans, and its abundance determines PET status.

Aims/hypothesis Bariatric surgery is an effective treatment for severe obesity, as in addition to dramatic weight loss, co-morbidities such as type 2 diabetes are frequently resolved. Although altered gastrointestinal peptide hormone secretion and its relationship with post-surgical improvements in insulin sensitivity has been studied, much less is known about long-term changes in pancreatic and adipose tissue-derived hormones. Our objective was to conduct a comprehensive longitudinal investigation of the endocrine changes following Roux-en-Y gastric bypass surgery (RYGBP), focusing on pancreatic and adipocyte hormones and systemic markers of inflammation. Methods Nineteen severely obese women (BMI 45.6± 1.6 kg/m2) were studied prior to RYGBP, and at 1, 3, 6, and 12 months after RYGBP. Body composition was assessed before surgery and at 1 and 12 months. Results Pre-surgical adiposity was correlated with circulating adipocyte hormones (leptin, visfatin) and inflammatory molecules (IL-6, high sensitivity C-reactive protein [hsCRP], monocyte chemoattractant protein-1). As expected, RYGBP reduced fat mass and fasting insulin and glucose concentrations. In addition, reductions of fasting pancreatic polypeptide (PP) and glucagon concentrations were observed at 1 and 3 months, respectively. In the 12 months following RYGBP, concentrations of most adipocyte hormones (leptin, acylation-stimulating hormone and visfatin, but not retinol-binding hormone-4) and inflammatory molecules (IL-6, hsCRP and soluble intracellular adhesion molecule-1) were significantly reduced. Reductions of insulin resistance (measured by homeostasis model assessment of insulin resistance) were independently associated with changes of glucagon, visfatin and PP. Pre-surgical HMW adiponectin concentrations independently predicted losses of body weight and fat mass. Conclusions/interpretation These results suggest that pancreatic and adipocyte hormones may contribute to the long-term resolution of insulin resistance after RYGBP.

Fructose consumption in the USA has increased over the past three decades. During this time, obesity, insulin resistance and the metabolic syndrome have also increased in prevalence. While diets high in fructose have been shown to promote insulin resistance and increase TAG concentrations in animals, there are insufficient data available regarding the long-term metabolic effects of fructose consumption in humans. The objective of the present study was to investigate the metabolic effects of 10-week consumption of fructose-sweetened beverages in human subjects under energy-balanced conditions in a controlled research setting. Following a 4-week weight-maintaining complex carbohydrate diet, seven overweight or obese (BMI 26·8 -33·3 kg/m 2 ) postmenopausal women were fed an isoenergetic intervention diet, which included a fructose-sweetened beverage with each meal, for 10 weeks. The intervention diet provided 15 % of energy from protein, 30 % from fat and 55 % from carbohydrate (30 % complex carbohydrate, 25 % fructose). Fasting and postprandial glucose, insulin, TAG and apoB concentrations were measured. Fructose consumption increased fasting glucose concentrations and decreased meal-associated glucose and insulin responses (P¼0·0002, P¼ 0·007 and P¼ 0·013, respectively). Moreover, after 10 weeks of fructose consumption, 14 h postprandial TAG profiles were significantly increased, with the area under the curve at 10 weeks being 141 % higher than at baseline (P¼ 0·04). Fructose also increased fasting apoB concentrations by 19 % (P¼ 0·043 v. baseline). In summary, consumption of fructose-sweetened beverages increased postprandial TAG and fasting apoB concentrations, and the present results suggest that long-term consumption of diets high in fructose could lead to an increased risk of CVD.