Diabetes mellitus is a product of low insulin sensibility and pancreatic β-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.

The adaptations promoted by GC treatment in adipose metabolism seemed to be mainly due to the increased activity of enzymes that supply the NADPH required for lipogenesis than to the increase in enzymes that more directly deal with fatty acid synthesis itself.

Melatonin, the main hormone produced by the pineal gland, is secreted in a circadian manner (24-hr period), and its oscillation influences several circadian biological rhythms, such as the regulation of clock genes expression (chronobiotic effect) and the modulation of several endocrine functions in peripheral tissues. Assuming that the circadian synchronization of clock genes can play a role in the regulation of energy metabolism and it is influenced by melatonin, our study was designed to assess possible alterations as a consequence of melatonin absence on the circadian expression of clock genes in the epididymal adipose tissue of male Wistar rats and the possible metabolic repercussions to this tissue. Our data show that pinealectomy indeed has impacts on molecular events: it abolishes the daily pattern of the expression of Clock, Per2, and Cry1 clock genes and Pparγ expression, significantly increases the amplitude of daily expression of Rev-erbα, and affects the pattern of and impairs adipokine production, leading to a decrease in leptin levels. However, regarding some metabolic aspects of adipocyte functions, such as its ability to synthesize triacylglycerols from glucose along 24 hr, was not compromised by pinealectomy, although the daily profile of the lipogenic enzymes expression (ATP-citrate lyase, malic enzyme, fatty acid synthase, and glucose-6-phosphate dehydrogenase) was abolished in pinealectomized animals.

Obesity results from critical periods of positive energy balance characterized by caloric intake greater than energy expenditure. This disbalance promotes adipose tissue dysfunction which is related to other comorbidities. Melatonin is a low-cost therapeutic agent and studies indicate that its use may improve obesity-related disorders. To evaluate if the melatonin is efficient in delaying or even blocking the damages caused by excessive ingestion of a high-fat diet (HFD) in mice, as well as improving the inflammatory profile triggered by obesity herein, male C57BL/6 mice of 8 weeks were induced to obesity by a HFD and treated for 10 weeks with melatonin. The results demonstrate that melatonin supplementation attenuated serum triglyceride levels and total and LDL cholesterol and prevented body mass gain through a decreased lipogenesis rate and increased lipolytic capacity in white adipocytes, with a concomitant increment in oxygen consumption and Pgc1a and Prdm16 expression. Altogether, these effects prevented adipocyte hypertrophy caused by HFD and reflected in decreased adiposity. Finally, melatonin supplementation reduced the crown-like-structure (CLS) formation, characteristic of the inflammatory process by macrophage infiltration into white adipose tissue of obese subjects, as well as decreased the gene expression of inflammation-related factors, such as leptin and MCP1. Thus, the melatonin can be considered a potential therapeutic agent to attenuate the metabolic and inflammatory disorders triggered by obesity.

Obesity is defined as a condition of abnormal or excessive fat accumulation in white adipose tissue that results from the exacerbated consumption of calories associated with low energy expenditure. Fat accumulation in both adipose tissue and other organs contributes to a systemic inflammation leading to the development of metabolic disorders such as type 2 diabetes, hypertension, and dyslipidemia. Melatonin is a potent antioxidant and improves inflammatory processes and energy metabolism. Using male mice fed a high-fat diet (HFD—59% fat from lard and soybean oil; 9:1) as an obesity model, we investigated the effects of melatonin supplementation on the prevention of obesity-associated complications through an analysis of plasma biochemical profile, body and fat depots mass, adipocytes size and inflammatory cytokines expression in epididymal (EPI) adipose depot. Melatonin prevented a gain of body weight and fat depot mass as well as adipocyte hypertrophy. Melatonin also reversed the increase of total cholesterol, triglycerides and LDL-cholesterol. In addition, this neurohormone was effective in completely decreasing the inflammatory cytokines leptin and resistin in plasma. In the EPI depot, melatonin reversed the increase of leptin, Il-6, Mcp-1 and Tnf-α triggered by obesity. These data allow us to infer that melatonin presents an anti-obesity effect since it acts to prevent the progression of pro-inflammatory markers in the epididymal adipose tissue together with a reduction in adiposity.

No abstract

The incidence of obese people worldwide is increasing every year and accumulating evidence indicates that dysregulated expression of adipokines, caused by excess adiposity and adipocyte dysfunction, has been linked to the pathogenesis of obesity‐linked complications. Melatonin, a hormone responsible for the synchronization of mammalian circadian rhythms, is related to beneficial effects on the control of obesity and its complications. In this work we evaluated the effects of melatonin supplementation on the production of adipokines in epididydimal (EPI) and inguinal (ING) fat depots from obese animals induced by a high‐fat‐diet (HFD). Male C57Bl/6j mice were divided into 3 groups: CO, animals fed with control diet; Obese, animals fed with HFD and Obese + melatonin, animals fed with HFD and supplemented with melatonin (1mg/kg). Melatonin presented a preventive effect on body weight gain and slowed down the effects on food and energy efficiency triggered by HFD. Adiponectin, IL‐6, leptin, and TNF‐α gene expression in ING and EPI fat depots were analysed. It was observed an increase (by 55 %, p <0.05) in adiponectin mRNA in ING depot when the animals received melatonin. There was an increase (3,7‐fold, p <0.05) in the IL‐6 mRNA expression in the EPI depot (but not in ING) in HFD group, that was prevented by melatonin supplementation. The same increase was observed on leptin expression in EPI adipose depot (6‐fold, p <0.05) from animals fed with HFD. Again, melatonin supplementation completely abolished this effect. Similarly, there was an increase (by 23‐fold, p <0.05) in the expression of this gene in the ING depot from HFD animals, and herein, we observed only a prevention trend (p = 0.0514) by melatonin on leptin mRNA in this fat depot. In both, EPI and ING depots, TNF‐α mRNA was significantly increased (by 5‐fold and 7‐fold respectively, p <0.05) in the HFD as compared to the CO group, but the melatonin supplementation not decreased this parameter. The protein analysis in these tissues (ING and EPI) performed by Elisa, showed that IL‐6 protein was increased (68%, p <0.05) in EPI fat depot from HFD group when compared to CO. This elevation was completely prevented when the animals were supplemented with melatonin. By the other side, no changes were observed between the groups concerning IL‐6 secretion in ING depot. The results obtained herein suggest that melatonin supplementation improves the adipokines expression in animais with obesity induced by a HFD, that is, it increases adiponectin while reducing the expression of inflammatory cytokines in adipose tissues. Together, these results show that melatonin supplementation had an protetive action on obesity complicationsSupport or Funding InformationFapesp (2015/03554‐2)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Biological rhythms, besides being under melatonin control, are also controlled by genetic mechanisms, which inform to neuronal and peripheral structures about circadian rhythms. Circadian system are driven by a series of interacting clock genes resulting in 24 hour cycles of gene expression. Clock genes may interact with metabolic genes and regulate their transcription, promoting a proper homeostasis. Disturbances in the rhythm of these genes can promote overweight and increased abdominal fat deposition leading to obesity and metabolic syndrome. Thus, the present study aimed to investigate the circadian rhythm of gene expression of clock genes, and, metabolic genes in pinealectomized animals. One month after pinealectomy, pinealectomized (Pinx) and control (Ctl) animals were sacrificed in different zeitgeber times (Zts: 0,4,8,12,16,20,24). Epididymal fat pad was removed and processed for Pparγ, Bmal1, Clock, Cry1 and Rev‐erbα gene expression. These genes were analyzed by quantitative reverse‐transcriptase PCR. Daily curves for clock and metabolic genes were tested with Anova‐one way and Cosinor analysis. Results: a) Cry 1 circadian rhythm was lost in pinealectomized rats (p<0.05); b) Bmal 1 and Clock daily oscillation did not change in the absence of melatonin; c) the expression of Rev‐erbα increased in Pinx rats (p<0.05); e) Pparγ temporal pattern was lost in Pinx rats. Although it was not observed changes in body weight and in epididymal fat depots, it was found significant differences in the gene expression of clock genes Cry1 and Rev‐erbα. Also the Pparγ temporal pattern has been altered in Pinx animals. Since it is already known that changes in the expression of these clock genes are associated with obesity‐related traits, probably the long‐term changes in these genes could be crucial for the development of a disorder of energy metabolism. Grant Funding Source: Supported by Fapesp