Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.

When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet-fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity.

Adipose tissue sensitivity to radiation exposure.

Treatment of cancer using radiation can be significantly compromised by the development of severe acute and late damage to normal tissue. Treatments that either reduce the risk and severity of damage or that facilitate the healing of radiation injuries are being developed, including autologous adipose tissue grafts to repair tissue defects or involutional disorders that result from tumor resection. Adipose tissue is specialized in energy storage and contains different cell types, including preadipocytes, which could be used for autologous transplantation. It has long been considered a poorly proliferative connective tissue; however, the acute effects of ionizing radiation on adipose tissue have not been investigated. Therefore, the aim of this study was to characterize the alterations induced in adipose tissue by total body irradiation. A severe decrease in proliferating cells, as well as a significant increase in apoptotic cells, was observed in vivo in inguinal fat pads following irradiation. Additionally, irradiation altered the hematopoietic population. Decreases in the proliferation and differentiation capacities of non-hematopoietic progenitors were also observed following irradiation. Together, these data demonstrate that subcutaneous adipose tissue is very sensitive to irradiation, leading to a profound alteration of its developmental potential. This damage could also alter the reconstructive properties of adipose tissue and, therefore, calls into question its use in autologous fat transfer following radiotherapy.

Melatonin reduces body weight gain in Sprague Dawley rats with diet-induced obesity.

Melatonin is involved in the regulation of seasonal obesity in various species, including some rodents. This involvement has been demonstrated in nonphotoperiodic rodents like rats, but only in models of enhanced body weight such as genetically obese or middle-aged rats. The aim of this investigation was to determine the effects of melatonin on body weight and metabolic parameters in a model closer to that observed in Western populations, i.e. Sprague Dawley rats fed a high-fat diet. They were treated for 3 wk with melatonin (30 mg/kg) 4 h after lights-on [Zeitgeber time (ZT) 4] or 1 h before lights-out (ZT11). Given at ZT11, melatonin decreased body weight gain and feed efficiency by half. Melatonin had no effect on plasma insulin level, but it decreased plasma glucose (13%), leptin (28%), and triglyceride (28%) levels. Furthermore, in pinealectomized high-fat diet rats, body weight gain and feed efficiency were increased 4 wk after surgery. Adipose tissue weight, insulinemia, and glycemia had a tendency to increase. Treatment with melatonin prevented in part these changes. These data demonstrate that melatonin may act as a regulator of body weight in a model of obesity and may prevent some of the side effects on glucose homeostasis such as decreased insulin sensitivity.

Raising HDL with CETP inhibitor torcetrapib improves glucose homeostasis in dyslipidemic and insulin resistant hamsters.

We investigated whether raising HDL-cholesterol levels with cholesteryl ester transfer protein (CETP) inhibition improves glucose homeostasis in dyslipidemic and insulin resistant hamsters. Compared with vehicle, torcetrapib 30 mg/kg/day (TOR) administered for 10 days significantly increased by ∼40% both HDL-cholesterol levels and 3H-tracer appearance in HDL after 3H-cholesterol labeled macrophages i.p. injection. TOR significantly reduced fasting plasma triglycerides, glycerol and free fatty acids levels by 65%, 31% and 23%, respectively. TOR also reduced blood glucose levels and plasma insulin by 20% and 49% respectively, which led to a 60% reduction in HOMA-IR index (all p<0.01). After 3H-2-deoxyglucose and insulin injection, TOR significantly increased glucose uptake in oxidative soleus muscle, liver and heart by 26, 33 and 70%, respectively. Raising HDL levels with the CETP inhibitor torcetrapib improves glucose homeostasis in dyslipidemic and insulin resistant hamsters. Whether similar effect would be observed with other CETP inhibitors should be investigated.

An adiponectin-like molecule with antidiabetic properties.

Adiponectin increases glucose transport, reduces inflammation, and controls vascular functions. Hence, we propose that treatment with a recombinant globular domain of adiponectin (rgAd110-244) has significant therapeutic potential to treat insulin resistance. Mice were fed for 3 months on a high-fat diet (HFD) to induce insulin resistance, diabetes, and moderate weight gain. The mice were first infused iv with different doses of rgAd110-244 (0.12, 0.4, and 1.2 microg/kg x min) for 5 h. Basal and insulin-sensitive glucose use rates were assessed by the use of a submaximal rate of insulin in the awake free-moving mouse. rgAd110-244 reduced, with dose dependence, epinephrine-induced hyperglycemia and HFD-induced insulin resistance by increasing whole-body glucose use (35% at the highest dose) and glycolysis rates. Similarly, the reduction of plasma free fatty acid concentrations by insulin was dramatically improved. Basal hepatic glucose production was unchanged by rgAd110-244 infusion. This acute rgAd110-244 treatment improved glucose homeostasis and was associated with an increased content of muscle phospho-Akt, glycogen synthase kinase-3beta, and AMP-activated kinase. Second, HFD mice were chronically treated with sc rgAd110-244 injections (10, 30, and 100 microg/kg). Fasting glycemia and insulin-sensitive glucose use were improved by rgAd110-244 at the highest dose at completion of the treatment, with concomitant reduction in body weight gain. We here show for the first time that a recombinant adiponectin fragment (110-244 amino acids called rgAd110-244) is able to treat insulin-resistant diabetes. Our results strongly suggest further pharmacological investigation of rgAd110-244 with the objective of developing a new treatment of insulin-resistant diabetes.

From heterogeneity to plasticity in adipose tissues: site-specific differences.

In mammals, two types of adipose tissues are present, brown (BAT) and white (WAT). WAT itself can be divided into subcutaneous and internal fat deposits. All these tissues have been shown to present a great tissue plasticity, and recent data emphasized on the multiple differentiation potentials obtained from subcutaneous WAT. However, no study has compared the heterogeneity of stroma-vascular fraction (SVF) cells and their differentiation potentials according to the localization of the fat pad. This study clearly demonstrates that WAT and BAT present different antigenic features and differentiation potentials. WAT by contrast to BAT contains a large population of hematopoietic cells composed essentially of macrophages and hematopoietic progenitor cells. In WAT, the non-hematopoietic population is mainly composed of mesenchymal stem cell (MSC)-like but contains also a significant proportion of immature cells, whereas in BAT, the stromal cells do not present the same phenotype. Internal and subcutaneous WAT present some discrete differences in the phenotype of their cell populations. WAT derived SVF cells give rise to osteoblasts, endothelial cells, adipocytes, hematopoietic cells, and cardiomyoblasts only from inguinal cells. By contrast, BAT derived SVF cells display a reduced plasticity. Adipose tissues thus appear as complex tissues composed of different cell subsets according to the location of fat pads. Inguinal WAT appears as the most plastic adipose tissue and represents a potential and suitable source of stem cell, considering its easy sampling as a major advantage for cell therapy.