The mechanisms involved in the increased adiposity induced by interruption of regular physical exercise practice.

AIMS: We investigated the effects of physical detraining on lipogenesis/lipolysis and cellularity (apoptosis/adipogenesis) in rat subcutaneous (inguinal; SC) and visceral (retroperitoneal; RP) white adipose depots. MAIN METHODS: Three groups of male Wistar rats (6-wk old) were studied: (1) (T) trained for 12 weeks; (2) (D) trained for 8 weeks and detrained for 4 weeks; and (3) (S) age-matched sedentary. Training consisted of treadmill running sessions (1 h/day, 5 days/week, 50-60% maximal race capacity). KEY FINDINGS: Physical detraining increased glucose oxidation, lipogenesis, and adipocyte size in the SC and RP depots. The number of apoptotic SC adipocytes was reduced by 53% in the T (p < 0.0001) and by 43% in the D (p < 0.001) as compared with S. RP adipocyte apoptosis in the T and D was 9.48% and 10.9% greater compared to the S, respectively (p < 0.05). In the SC stromal vascular fraction (SVF) of D rats, adiponectin, sterol regulatory element binding protein (SREBP)-1c, Peroxisome proliferator-activated receptor gamma (PPARγ), and Perilipin A mRNA expressions were more pronounced than S group, suggesting a more intense adipogenesis. This putative adipogenic effect was not observed in the RP depot. The physical detraining promoted rapid increase in the SC and RP depots however not through the same mechanisms. SIGNIFICANCE: Physical detraining induced fat cell hypertrophy (increase of lipogenesis) in both SC and RP whereas hyperplasia (increase of adipogenesis and reduction of apoptosis) was found in SC only. These results indicate the mechanism associated with obesogenic effects of detraining varies with the fat depot.

Neonatal streptozotocin-induced diabetes in mothers promotes metabolic programming of adipose tissue in male rat offspring.

AIMS: Maternal hyperglycemia during pregnancy can lead to fetal changes, like macrosomia or obesity in adultlife. Experimentalmodels of diabetes have been studied to evaluate the consequences of offspring lipidmetabolism. This study aimed to investigate the metabolic changes in adipose tissue of offspring of streptozotocininduced diabetic mothers during neonatal period. MAIN METHODS: Diabetes was induced in female rats by streptozotocin administration on 5th day of life. In adulthood, female rats were bred with control male rats. Male puppies were sacrificed on 12th week of life and epididymal (EP) and subcutaneous (SC) adipose fat pads were excised and weighted. Adipocytes were isolated and evaluated for basal and insulin-stimulated 2-deoxyglucose uptake, oxidation of glucose into CO2, and incorporationof glucose into lipids and lipolytic capacity. KEY FINDINGS: Bodyweight, EP fat padweight and diameter of adipocytes fromoffspring of diabeticmothers were increased in comparison to offspring of control mothers. EP adipocytes from offspring of diabetic mothers presented increased basal and insulin stimulated glucose uptake in comparison to control ones. Similar pattern was observed for glucose oxidation into CO2 and incorporation into lipids. However, significant difference in lipolytic capacity in vitrowas not observed. Protein content of GLUT4, insulin receptor and acetyl-CoA carboxylase was significantly increased in EP fat pad of offspring of diabetic mothers in relation to control group. SIGNIFICANCE: Metabolic programming occurred in the adipose tissue of offspring of diabetic mothers, increasing its capacity to store lipids with no changes in lipolytic capacity.

Pioglitazone treatment increases survival and prevents body weight loss in tumor-bearing animals: possible anti-cachectic effect.

Cachexia is a multifactorial syndrome characterized by profound involuntary weight loss, fat depletion, skeletal muscle wasting, and asthenia; all symptoms are not entirely attributable to inadequate nutritional intake. Adipose tissue and skeletal muscle loss during cancer cachexia development has been described systematically. The former was proposed to precede and be more rapid than the latter, which presents a means for the early detection of cachexia in cancer patients. Recently, pioglitazone (PGZ) was proposed to exhibit anti-cancer properties, including a reduction in insulin resistance and adipose tissue loss; nevertheless, few studies have evaluated its effect on survival. For greater insight into a potential anti-cachectic effect due to PGZ, 8-week-old male Wistar rats were subcutaneously inoculated with 1 mL (2×107) of Walker 256 tumor cells. The animals were randomly assigned to two experimental groups: TC (tumor + saline-control) and TP5 (tumor + PGZ/5 mg). Body weight, food ingestion and tumor growth were measured at baseline and after removal of tumor on days 7, 14 and 26. Samples from different visceral adipose tissue (AT) depots were collected on days 7 and 14 and stored at -80o C (5 to 7 animals per day/group). The PGZ treatment showed an increase in the survival average of 27.3% (P< 0.01) when compared to TC. It was also associated with enhanced body mass preservation (40.7 and 56.3%, p< 0.01) on day 14 and 26 compared with the TC group. The treatment also reduced the final tumor mass (53.4%, p<0.05) and anorexia compared with the TC group during late-stage cachexia. The retroperitoneal AT (RPAT) mass was preserved on day 7 compared with the TC group during the same experimental period. Such effect also demonstrates inverse relationship with tumor growth, on day 14. Gene expression of PPAR-γ, adiponectin, LPL and C/EBP-α from cachectic rats was upregulated after PGZ. Glucose uptake from adipocyte cells (RPAT) was entirely re-established due to PGZ treatment. Taken together, the results demonstrate beneficial effects of PGZ treatment at both the early and final stages of cachexia.

Cessation of physical exercise changes metabolism and modifies the adipocyte cellularity of the periepididymal white adipose tissue in rats.

All of the adaptations acquired through physical training are reversible with inactivity. Although significant reductions in maximal oxygen uptake (Vo2max) can be observed within 2 to 4 wk of detraining, the consequences of detraining on the physiology of adipose tissue are poorly known. Our aim was therefore to investigate the effects of discontinuing training (physical detraining) on the metabolism and adipocyte cellularity of rat periepididymal (PE) adipose tissue. Male Wistar rats, aged 6 wk, were divided into three groups and studied for 12 wk under the following conditions: 1) trained (T) throughout the period; 2) detrained (D), trained during the first 8 wk and detrained during the remaining 4 wk; and 3) age-matched sedentary (S). Training consisted of treadmill running sessions (1 h/day, 5 days/wk, 50-60% Vo2max). The PE adipocyte size analysis revealed significant differences between the groups. The adipocyte cross-sectional area (in µm(2)) was significantly larger in D than in the T and S groups (3,474 ± 68.8; 1,945.7 ± 45.6; 2,492.4 ± 49.08, respectively, P < 0.05). Compared with T, the isolated adipose cells (of the D rats) showed a 48% increase in the ability to perform lipogenesis (both basal and maximally insulin-stimulated) and isoproterenol-stimulated lipolysis. No changes were observed with respect to unstimulated lipolysis. A 15% reduction in the proportion of apoptotic adipocytes was observed in groups T and D compared with group S. The gene expression levels of adiponectin and PPAR-gamma were upregulated by factors of 3 and 2 in D vs. S, respectively. PREF-1 gene expression was 3-fold higher in T vs. S. From these results, we hypothesize that adipogenesis was stimulated in group D and accompanied by significant adipocyte hypertrophy and an increase in the lipogenic capacity of the adipocytes. The occurrence of apoptotic nuclei in PE fat cells was reduced in the D and T rats; these results raise the possibility that the adipose tissue changes after detraining are obesogenic.

Metabolic disorders and adipose tissue insulin responsiveness in neonatally STZ-induced diabetic rats are improved by long-term melatonin treatment.

Diabetes mellitus is a product of low insulin sensibility and pancreatic ß-cell insufficiency. Rats with streptozotocin-induced diabetes during the neonatal period by the fifth day of age develop the classic diabetic picture of hyperglycemia, hypoinsulinemia, polyuria, and polydipsia aggravated by insulin resistance in adulthood. In this study, we investigated whether the effect of long-term treatment with melatonin can improve insulin resistance and other metabolic disorders in these animals. At the fourth week of age, diabetic animals started an 8-wk treatment with melatonin (1 mg/kg body weight) in the drinking water at night. Animals were then killing, and the sc, epididymal (EP), and retroperitoneal (RP) fat pads were excised, weighed, and processed for adipocyte isolation for morphometric analysis as well as for measuring glucose uptake, oxidation, and incorporation of glucose into lipids. Blood samples were collected for biochemical assays. Melatonin treatment reduced hyperglycemia, polydipsia, and polyphagia as well as improved insulin resistance as demonstrated by constant glucose disappearance rate and homeostasis model of assessment-insulin resistance. However, melatonin treatment was unable to recover body weight deficiency, fat mass, and adipocyte size of diabetic animals. Adiponectin and fructosamine levels were completely recovered by melatonin, whereas neither plasma insulin level nor insulin secretion capacity was improved in diabetic animals. Furthermore, melatonin caused a marked delay in the sexual development, leaving genital structures smaller than those of nontreated diabetic animals. Melatonin treatment improved the responsiveness of adipocytes to insulin in diabetic animals measured by tests of glucose uptake (sc, EP, and RP), glucose oxidation, and incorporation of glucose into lipids (EP and RP), an effect that seems partially related to an increased expression of insulin receptor substrate 1, acetyl-coenzyme A carboxylase and fatty acid synthase. In conclusion, melatonin treatment was capable of ameliorating the metabolic abnormalities in this particular diabetes model, including insulin resistance and promoting a better long-term glycemic control.

Kinin B1 receptor in adipocytes regulates glucose tolerance and predisposition to obesity.

BACKGROUND: Kinins participate in the pathophysiology of obesity and type 2 diabetes by mechanisms which are not fully understood. Kinin B(1) receptor knockout mice (B(1) (-/-)) are leaner and exhibit improved insulin sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that kinin B(1) receptors in adipocytes play a role in controlling whole body insulin action and glucose homeostasis. Adipocytes isolated from mouse white adipose tissue (WAT) constitutively express kinin B(1) receptors. In these cells, treatment with the B(1) receptor agonist des-Arg(9)-bradykinin improved insulin signaling, GLUT4 translocation, and glucose uptake. Adipocytes from B(1) (-/-) mice showed reduced GLUT4 expression and impaired glucose uptake at both basal and insulin-stimulated states. To investigate the consequences of these phenomena to whole body metabolism, we generated mice where the expression of the kinin B(1) receptor was limited to cells of the adipose tissue (aP2-B(1)/B(1) (-/-)). Similarly to B(1) (-/-) mice, aP2-B(1)/B(1) (-/-) mice were leaner than wild type controls. However, exclusive expression of the kinin B(1) receptor in adipose tissue completely rescued the improved systemic insulin sensitivity phenotype of B(1) (-/-) mice. Adipose tissue gene expression analysis also revealed that genes involved in insulin signaling were significantly affected by the presence of the kinin B(1) receptor in adipose tissue. In agreement, GLUT4 expression and glucose uptake were increased in fat tissue of aP2-B(1)/B(1) (-/-) when compared to B(1) (-/-) mice. When subjected to high fat diet, aP2-B(1)/B(1) (-/-) mice gained more weight than B(1) (-/-) littermates, becoming as obese as the wild types. CONCLUSIONS/SIGNIFICANCE: Thus, kinin B(1) receptor participates in the modulation of insulin action in adipocytes, contributing to systemic insulin sensitivity and predisposition to obesity.

Effects of antipsychotics with different weight gain liabilities on human in vitro models of adipose tissue differentiation and metabolism.

Weight gain and metabolic abnormalities are serious side effects associated with the use of several second generation antipsychotics (SGA). The adipose tissue has been considered a direct SGA target involved in the development of these adverse effects. Recent studies, mainly using murine cells, have suggested that SGA increase both adipogenesis of preadipocytes and lipid accumulation in mature adipocytes. However, to date there has been little research comparing the effects of antipsychotics with different propensities to induce weight gain on human in vitro models of white adipose tissue neoformation and metabolism. The present study aimed to investigate the effects of antipsychotics either strongly associated with weight gain, such as the SGA clozapine and olanzapine, or not, such as the SGA ziprasidone and the classical antipsychotic haloperidol, on proliferation and adipocyte differentiation of human adipose-derived stem cells (ADSCs) and lipogenesis in human mature adipocytes. Whereas ziprasidone induced elevated levels of cell death during adipogenesis and could not be investigated further, we observed that clozapine, olanzapine and haloperidol had slight stimulatory effects on the transcriptional program of ADSCs adipogenesis. However, the observed changes in adipocyte-specific genes were not accompanied by a significant increase in triglyceride accumulation within differentiated adipocytes. Our data also showed that these three antipsychotics displayed inhibitory effects on the proliferation rates of undifferentiated ADSCs. Regarding mature adipocyte metabolism, we observed that olanzapine slightly inhibited insulin-stimulated lipogenesis at the highest concentration used, and haloperidol exerted the strongest inhibitory effects on both basal and insulin-stimulated lipogenesis. Taken together, our results suggest that a direct and potent effect of clozapine and olanzapine on adipose tissue biology is not an important mechanism by which these SGA induce metabolic disturbances in humans. On the other hand, the haloperidol-mediated downregulation of the lipogenic capacity of human adipose tissue may be a possible mechanism contributing to its lower propensity to induce serious metabolic side effects.