Photobiomodulation with Blue Light on Wound Healing: A Scoping Review.

BACKGROUND: Photobiomodulation consists of inducing healing by irradiating light. This scoping review investigates the effect of blue light on the healing process. METHODS: The MEDLINE, Web of Science, Scopus, and CINAHL databases were searched. Two reviewers independently examined the search results and extracted data from the included studies. A descriptive analysis was performed. RESULTS: Twenty-two articles were included. Studies were categorized as in vitro/mixed, preclinical, and clinical. The power density used was 10-680 mW/cm2 in most of the in vitro/preclinical studies, the irradiation time ranged from 5 s to 10 min, and different wavelengths and energy densities were used. In clinical studies, the wavelength ranged from 405 to 470 nm, and the energy density varied from 1.5 to 30 J/cm2. CONCLUSIONS: A low energy density (<20 J/cm2) was able to stimulate the different cell types and proteins involved in healing, while a high energy density, 20.6-50 J/cm2, significantly reduced cell proliferation, migration, and metabolism. There is a great variety of device parameters among studies, and this makes it difficult to conclude what the best technical specifications are. Thus, further studies should be performed in order to define the appropriate parameters of light to be used.

Maternal obesity damages the median eminence blood-brain barrier structure and function in the progeny: the beneficial impact of cross-fostering by lean mothers.

Maternal obesity is an important risk factor for obesity, cardiovascular, and metabolic diseases in the offspring. Studies have shown that it leads to hypothalamic inflammation in the progeny, affecting the function of neurons regulating food intake and energy expenditure. In adult mice fed a high-fat diet, one of the hypothalamic abnormalities that contribute to the development of obesity is the damage of the blood-brain barrier (BBB) at the median eminence-arcuate nucleus (ME-ARC) interface; however, how the hypothalamic BBB is affected in the offspring of obese mothers requires further investigation. Here, we used confocal and transmission electron microscopy, transcript expression analysis, glucose tolerance testing, and a cross-fostering intervention to determine the impact of maternal obesity and breastfeeding on BBB integrity at the ME-ARC interface. The offspring of obese mothers were born smaller; conversely, at weaning, they presented larger body mass and glucose intolerance. In addition, maternal obesity-induced structural and functional damage of the offspring's ME-ARC BBB. By a cross-fostering intervention, some of the defects in barrier integrity and metabolism seen during development in an obesogenic diet were recovered. The offspring of obese dams breastfed by lean dams presented a reduction of body mass and glucose intolerance as compared to the offspring continuously exposed to an obesogenic environment during intrauterine and perinatal life; this was accompanied by partial recovery of the anatomical structure of the ME-ARC interface, and by the normalization of transcript expression of genes coding for hypothalamic neurotransmitters involved in energy balance and BBB integrity. Thus, maternal obesity promotes structural and functional damage of the hypothalamic BBB, which is, in part, reverted by lactation by lean mothers.NEW & NOTEWORTHY Maternal dietary habits directly influence offspring health. In this study, we aimed at determining the impact of maternal obesity on BBB integrity. We show that DIO offspring presented a leakier ME-BBB, accompanied by changes in the expression of transcripts encoding for endothelial and tanycytic proteins, as well as of hypothalamic neuropeptides. Breastfeeding in lean dams was sufficient to protect the offspring from ME-BBB disruption, providing a preventive strategy of nutritional intervention during early life.

Interleukin-6 actions in the hypothalamus protects against obesity and is involved in the regulation of neurogenesis.

BACKGROUND: Interleukin-6 (IL6) produced in the context of exercise acts in the hypothalamus reducing obesity-associated inflammation and restoring the control of food intake and energy expenditure. In the hippocampus, some of the beneficial actions of IL6 are attributed to its neurogenesis-inducing properties. However, in the hypothalamus, the putative neurogenic actions of IL6 have never been explored, and its potential to balance energy intake can be an approach to prevent or attenuate obesity. METHODS: Wild-type (WT) and IL6 knockout (KO) mice were employed to study the capacity of IL6 to induce neurogenesis. We used cell labeling with Bromodeoxyuridine (BrdU), immunofluorescence, and real-time PCR to determine the expression of markers of neurogenesis and neurotransmitters. We prepared hypothalamic neuroprogenitor cells from KO that were treated with IL6 in order to provide an ex vivo model to further characterizing the neurogenic actions of IL6 through differentiation assays. In addition, we analyzed single-cell RNA sequencing data and determined the expression of IL6 and IL6 receptor in specific cell types of the murine hypothalamus. RESULTS: IL6 expression in the hypothalamus is low and restricted to microglia and tanycytes, whereas IL6 receptor is expressed in microglia, ependymocytes, endothelial cells, and astrocytes. Exogenous IL6 reduces diet-induced obesity. In outbred mice, obesity-resistance is accompanied by increased expression of IL6 in the hypothalamus. IL6 induces neurogenesis-related gene expression in the hypothalamus and in neuroprogenitor cells, both from WT as well as from KO mice. CONCLUSION: IL6 induces neurogenesis-related gene expression in the hypothalamus of WT mice. In KO mice, the neurogenic actions of IL6 are preserved; however, the appearance of new fully differentiated proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons is either delayed or disturbed.

Interleukin-6 Expression by Hypothalamic Microglia in Multiple Inflammatory Contexts: A Systematic Review.

Interleukin-6 (IL-6) is a unique cytokine that can play both pro- and anti-inflammatory roles depending on the anatomical site and conditions under which it has been induced. Specific neurons of the hypothalamus provide important signals to control food intake and energy expenditure. In individuals with obesity, a microglia-dependent inflammatory response damages the neural circuits responsible for maintaining whole-body energy homeostasis, resulting in a positive energy balance. However, little is known about the role of IL-6 in the regulation of hypothalamic microglia. In this systematic review, we asked what types of conditions and stimuli could modulate microglial IL-6 expression in murine model. We searched the PubMed and Web of Science databases and analyzed 13 articles that evaluated diverse contexts and study models focused on IL-6 expression and microglia activation, including the effects of stress, hypoxia, infection, neonatal overfeeding and nicotine exposure, lipopolysaccharide stimulus, hormones, exercise protocols, and aging. The results presented in this review emphasized the role of "injury-like" stimuli, under which IL-6 acts as a proinflammatory cytokine, concomitant with marked microglial activation, which drive hypothalamic neuroinflammation. Emerging evidence indicates an important correlation of basal IL-6 levels and microglial function with the maintenance of hypothalamic homeostasis. Advances in our understanding of these different contexts will lead to the development of more specific pharmacological approaches for the management of acute and chronic conditions, like obesity and metabolic diseases, without disturbing the homeostatic functions of IL-6 and microglia in the hypothalamus.

Downregulation of HIF complex in the hypothalamus exacerbates diet-induced obesity.

Hypothalamic hypoxia-inducible factor-1 (HIF-1) can regulate whole-body energy homeostasis in response to changes in blood glucose, suggesting that it acts as a sensor for systemic energy stores. Here, we hypothesized that hypothalamic HIF-1 could be affected by diet-induced obesity (DIO). We used eight-week old, male C57Bl6 mice, fed normal chow diet or with high fat diet for 1, 3, 7, 14 and 28 days. The expression of HIF-1alpha and HIF-1beta was measured by PCR and western blotting and its hypothalamic distribution was evaluated by fluorescence microscopy. Inhibition of HIF-1beta in arcuate nucleus of hypothalamus was performed using stereotaxic injection of shRNA lentiviral particles and animals were grouped under normal chow diet or high fat diet for 14 days. Using bioinformatics, we show that in humans, the levels of HIF-1 transcripts are directly correlated with those of hypothalamic transcripts for proteins involved in inflammation, regulation of apoptosis, autophagy, and the ubiquitin/proteasome system; furthermore, in rodents, hypothalamic HIF-1 expression is directly correlated with the phenotype of increased energy expenditure. In mice, DIO was accompanied by increased HIF-1 expression. The inhibition of hypothalamic HIF-1 by injection of an shRNA resulted in a further increase in body mass, a decreased basal metabolic rate, increased hypothalamic inflammation, and glucose intolerance. Thus, hypothalamic HIF-1 is increased during DIO, and its inhibition worsens the obesity-associated metabolic phenotype. Thus, hypothalamic HIF-1 emerges as a target for therapeutic intervention against obesity.

TGF-ß1 down-regulation in the mediobasal hypothalamus attenuates hypothalamic inflammation and protects against diet-induced obesity.

BACKGROUND: The consumption of large amounts of dietary fats induces hypothalamic inflammation and impairs the function of the melanocortin system, leading to a defective regulation of caloric intake and whole-body energy expenditure. In mice fed a high-fat diet (HFD), TGF-ß1 expression was increased and NF-κB signaling was activated in proopiomelanocortin neurons, which plays an important role in the obesity-associated hypothalamic inflammation scenario. However, whether excessive hypothalamic TGF-ß1 impairs energy homeostasis remains unclear. OBJECTIVES: We aimed to investigate the role of diet-induced hypothalamic TGF-ß1 on inflammation and whole-body energy homeostasis. METHODS: A TGF-ß1 inhibitory lentiviral shRNA particle was stereotaxically injected bilaterally in the arcuate nucleus (ARC) of C57BL/6 mice fed a HFD. We assessed changes in body mass and adiposity, food intake, inflammatory markers, and the function of energy and glucose metabolism. RESULTS: TGF-ß1 down-regulation in the ARC-attenuated body-mass gain, reduced fat-mass accumulation, decreased hypothalamic inflammatory markers, and protected against HFD-induced lipohypertrophy of brown adipose tissue. In addition, the inhibition of hypothalamic TGF-ß1 increased the locomotor activity and improved whole-body lipid metabolism, which attenuated hepatic fat accumulation and serum triglyceride levels. No changes were observed in food intake and glucose homeostasis. CONCLUSION: Hypothalamic TGF-ß1 down-regulation attenuates hypothalamic inflammation and improves energy metabolism, resulting in lower body-mass gain and lower fat-mass accumulation, which protects mice from the development of obesity. Our data suggest that modulation of hypothalamic TGF-ß1 expression might be an effective strategy to treat obesity.

Defective regulation of POMC precedes hypothalamic inflammation in diet-induced obesity.

Obesity is the result of a long-term positive energy balance in which caloric intake overrides energy expenditure. This anabolic state results from the defective activity of hypothalamic neurons involved in the sensing and response to adiposity. However, it is currently unknown what the earliest obesity-linked hypothalamic defect is and how it orchestrates the energy imbalance present in obesity. Using an outbred model of diet-induced obesity we show that defective regulation of hypothalamic POMC is the earliest marker distinguishing obesity-prone from obesity-resistant mice. The early inhibition of hypothalamic POMC was sufficient to transform obesity-resistant in obesity-prone mice. In addition, the post-prandial change in the blood level of ß-endorphin, a POMC-derived peptide, correlates with body mass gain in rodents and humans. Taken together, these results suggest that defective regulation of POMC expression, which leads to a change of ß-endorphin levels, is the earliest hypothalamic defect leading to obesity.

MECHANISMS IN ENDOCRINOLOGY: Hypothalamic inflammation and nutrition.

Selected subpopulations of hypothalamic neurons play important roles in the regulation of whole body energy homeostasis. Studies have shown that the saturated fats present in large amounts in western diets can activate an inflammatory response in the hypothalamus, affecting the capacity of such neurons to respond appropriately to satiety and adipostatic signals. In the first part of this review, we will explore the mechanisms behind saturated fatty acid-induced hypothalamic dysfunction. Next, we will present and discuss recent studies that have identified the mechanisms that mediate some of the anti-inflammatory actions of unsaturated fatty acids in the hypothalamus and the potential for exploring these mechanisms to prevent or treat obesity.

Inflammation of the hypothalamus leads to defective pancreatic islet function.

Type 2 diabetes mellitus results from the complex association of insulin resistance and pancreatic ß-cell failure. Obesity is the main risk factor for type 2 diabetes mellitus, and recent studies have shown that, in diet-induced obesity, the hypothalamus becomes inflamed and dysfunctional, resulting in the loss of the perfect coupling between caloric intake and energy expenditure. Because pancreatic ß-cell function is, in part, under the control of the autonomic nervous system, we evaluated the role of hypothalamic inflammation in pancreatic islet function. In diet-induced obesity, the earliest markers of hypothalamic inflammation are present at 8 weeks after the beginning of the high fat diet; similarly, the loss of the first phase of insulin secretion is detected at the same time point and is restored following sympathectomy. Intracerebroventricular injection of a low dose of tumor necrosis factor α leads to a dysfunctional increase in insulin secretion and activates the expression of a number of markers of apoptosis in pancreatic islets. In addition, the injection of stearic acid intracerebroventricularly, which leads to hypothalamic inflammation through the activation of tau-like receptor-4 and endoplasmic reticulum stress, produces an impairment of insulin secretion, accompanied by increased expression of markers of apoptosis. The defective insulin secretion, in this case, is partially dependent on sympathetic signal-induced peroxisome proliferator receptor-γ coactivator Δα and uncoupling protein-2 expression and is restored after sympathectomy or following PGC1α expression inhibition by an antisense oligonucleotide. Thus, the autonomic signals generated in concert with hypothalamic inflammation can impair pancreatic islet function, a phenomenon that may explain the early link between obesity and defective insulin secretion.

Hypothalamic inflammation and obesity.

Obesity is one of the most prevalent diseases in the modern world. It results from the progressive loss of balance between food intake and whole body energy expenditure. Recent studies have shown that consumption of fat-rich diets induces hypothalamic inflammation and dysfunction which is characterized by defective response to anorexygenic and thermogenic hormones, such as leptin and insulin, leading to anomalous neurotransmitter production and favoring body mass gain. In this chapter, we present the main recent advances in this rapidly evolving field, focusing on the role of hypothalamic inflammation on the genesis of obesity.

Augmentation of insulin secretion by leucine supplementation in malnourished rats: possible involvement of the phosphatidylinositol 3-phosphate kinase/mammalian target protein of rapamycin pathway.

A regimen of low-protein diet induces a reduction of pancreatic islet function that is associated with development of metabolic disorders including diabetes and obesity afterward. In the present study, the influence of leucine supplementation on metabolic parameters, insulin secretion to glucose and to amino acids, as well as the levels of proteins that participate in the phosphatidylinositol 3-phosphate kinase (PI3K) pathway was investigated in malnourished rats. Four groups were fed with different diets for 12 weeks: a normal protein diet (17%) without (NP) or with leucine supplementation (NPL) or a low (6%)-protein diet without (LP) or with leucine supplementation (LPL). Leucine was given in the drinking water during the last 4 weeks. As indicated by the intraperitoneal glucose tolerance test, LPL rats exhibited increased glucose tolerance as compared with NPL group. Both NPL and LPL rats had higher circulating insulin levels than controls. The LPL rats also showed increased insulin secretion by pancreatic islets in response to glucose or arginine compared with those observed in islets from LP animals. Glucose oxidation was significantly reduced in NPL, LP, and LPL isolated islets as compared with NP; but no alteration was observed for leucine and glutamate oxidation among the 4 groups. Western blotting analysis demonstrated increased PI3K and mammalian target protein of rapamycin protein contents in LPL compared with LP islets. A significant increase in insulin-induced insulin receptor substrate 1-associated PI3K activation was also observed in LPL compared with LP islets. These findings indicate that leucine supplementation can augment islet function in malnourished rats and that activation of the PI3K/mammalian target protein of rapamycin pathway may play a role in this process.

Hypothalamic dysfunction in obesity.

The prevalence of obesity has grown to an alarming magnitude, affecting more than 300 million humans worldwide. Although in most instances obesity is caused by excessive caloric consumption, only recently have we begun to understand the mechanisms involved in the loss of balance between caloric intake and energy expenditure. In the hypothalamus, groups of specialized neurons provide the signals that, under physiological conditions, determine the stability of body mass. Recent studies have shown that under certain environmental and genetic conditions, this equilibrium is lost and body adiposity may increase. Here, we review the work that provided the basis for the current understanding of hypothalamic dysfunction and the genesis of obesity.

Diet-induced inflammation of the hypothalamus in obesity.

Dysfunction of specific hypothalamic neurons is regarded as an important mechanism predisposing to the development of obesity. Recent studies have revealed that the consumption of fat-rich foods can activate an inflammatory response in the hypothalamus, which disturbs the anorexigenic and thermogenic signals generated by the hormones leptin and insulin, leading in turn to anomalous body mass control. Depending on diet composition, cytokines are expressed in the hypothalamus, contributing to the activation of intracellular inflammatory signal transduction. At least 4 distinct signaling pathways have been identified and the molecular mechanisms leading to the impairment of the leptin and insulin actions have been determined. Here, we present the mechanisms involved in diet-induced resistance to leptin and insulin action in the hypothalamus and discuss some of the potential applications of this knowledge in the therapeutics of obesity.

UCP2 protects hypothalamic cells from TNF-alpha-induced damage.

Uncoupling protein 2 (UCP2) is highly expressed in the hypothalamus; however, little is known about the functions it exerts in this part of the brain. Here, we hypothesized that UCP2 protects hypothalamic cells from oxidative and pro-apoptotic damage generated by inflammatory stimuli. Intracerebroventricular injection of tumor necrosis factor alpha (TNF-alpha)-induced an increase of UCP2 expression in the hypothalamus, which was accompanied by increased expression of markers of oxidative stress and pro-apoptotic proteins. The inhibition of UCP2 expression by an antisense oligonucleotide enhanced the damaging effects of TNF-alpha. Conversely, increasing the hypothalamic expression of UCP2 by cold exposure reversed most of the effects of the cytokine. Thus, UCP2 acts as a protective factor against cellular damage induced by an inflammatory stimulus in the hypothalamus.

Distinct subsets of hypothalamic genes are modulated by two different thermogenesis-inducing stimuli.

Obesity results from an imbalance between food intake and energy expenditure, two vital functions that are tightly controlled by specialized neurons of the hypothalamus. The complex mechanisms that integrate these two functions are only beginning to be deciphered. The objective of this study was to determine the effect of two thermogenesis-inducing conditions, i.e., ingestion of a high-fat (HF) diet and exposure to cold environment, on the expression of 1,176 genes in the hypothalamus of Wistar rats. Hypothalamic gene expression was evaluated using a cDNA macroarray approach. mRNA and protein expressions were determined by reverse-transcription PCR (RT-PCR) and immunoblot. Cold exposure led to an increased expression of 43 genes and to a reduced expression of four genes. HF diet promoted an increased expression of 90 genes and a reduced expression of 78 genes. Only two genes (N-methyl-D-aspartate (NMDA) receptor 2B and guanosine triphosphate (GTP)-binding protein G-alpha-i1) were similarly affected by both thermogenesis-inducing conditions, undergoing an increment of expression. RT-PCR and immunoblot evaluations confirmed the modulation of NMDA receptor 2B and GTP-binding protein G-alpha-i1, only. This corresponds to 0.93% of all the responsive genes and 0.17% of the analyzed genes. These results indicate that distinct environmental thermogenic stimuli can modulate predominantly distinct profiles of genes reinforcing the complexity and multiplicity of the hypothalamic mechanisms that regulate energy conservation and expenditure.

Infliximab restores glucose homeostasis in an animal model of diet-induced obesity and diabetes.

TNF-alpha plays an important role in obesity-linked insulin resistance and diabetes mellitus by activating at least two serine kinases capable of promoting negative regulation of key elements of the insulin signaling pathway. Pharmacological inhibition of TNF-alpha is currently in use for the treatment of rheumatoid and psoriatic arthritis, and some case reports have shown clinical improvement of diabetes in patients treated with the TNF-alpha blocking monoclonal antibody infliximab. The objective of this study was to evaluate the effect of infliximab on glucose homeostasis and insulin signal transduction in an animal model of diabetes. Diabetes was induced in Swiss mice by a fat-rich diet. Glucose and insulin homeostasis were evaluated by glucose and insulin tolerance tests and by the hyperinsulinemic-euglycemic clamp. Signal transduction was evaluated by immunoprecipitation and immunoblotting assays. Short-term treatment with infliximab rapidly reduced blood glucose and insulin levels and glucose and insulin areas under the curve during a glucose tolerance test. Furthermore, infliximab increased the glucose decay constant during an insulin tolerance test and promoted a significant increase in glucose infusion rate during a hyperinsulinemic-euglycemic clamp. In addition, the clinical outcomes were accompanied by improved insulin signal transduction in muscle, liver, and hypothalamus, as determined by the evaluation of insulin-induced insulin receptor, insulin receptor substrate-1, and receptor substrate-2 tyrosine phosphorylation and Akt and forkhead box protein O1 serine phosphorylation. Thus, pharmacological inhibition of TNF-alpha may be an attractive approach to treat severely insulin-resistant patients with type 2 diabetes mellitus.

Phosphoinositide-specific inositol polyphosphate 5-phosphatase IV inhibits inositide trisphosphate accumulation in hypothalamus and regulates food intake and body weight.

The enzyme phosphatidylinositol 3-kinase (PI3-kinase) exerts an important role in the transduction of the anorexigenic and thermogenic signals delivered by insulin and leptin to first-order neurons of the arcuate nucleus in the hypothalamus. The termination of the intracellular signals generated by the activation of PI3-kinase depends on the coordinated activity of specific inositol phosphatases. Here we show that phosphoinositide-specific inositol polyphosphate 5-phosphatase IV (5ptase IV) is highly expressed in neurons of the arcuate and lateral nuclei of the hypothalamus. Upon intracerebroventricular (ICV) treatment with insulin, 5ptase IV undergoes a time-dependent tyrosine phosphorylation, which follows the same patterns of canonical insulin signaling through the insulin receptor, insulin receptor substrate-2, and PI3-kinase. To evaluate the participation of 5ptase IV in insulin action in hypothalamus, we used a phosphorthioate-modified antisense oligonucleotide specific for this enzyme. The treatment of rats with this oligonucleotide for 4 d reduced the hypothalamic expression of 5ptase IV by approximately 80%. This was accompanied by an approximately 70% reduction of insulin-induced tyrosine phosphorylation of 5ptase IV and an increase in basal accumulation of phosphorylated inositols in the hypothalamus. Finally, inhibition of hypothalamic 5ptase IV expression by the antisense approach resulted in reduced daily food intake and body weight loss. Thus, 5ptase IV is a powerful regulator of signaling through PI3-kinase in hypothalamus and may become an interesting target for therapeutics of obesity and related disorders.

Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus.

Obesity has reached epidemic proportions in several regions of the world. General changes in lifestyle, including consumption of fat-rich food, are among the most important factors leading to an unprecedented increase in the prevalence of this disease. Weight gain results from an imbalance between caloric intake and energy expenditure. Both of these parameters are under the tight control of specialized neurons of the hypothalamus that respond to peripheral anorexigenic and adipostatic signals carried by leptin and insulin. Here we show, by macroarray analysis, that high-fat feeding [hyperlipidic diet (HL)] induces the expression of several proinflammatory cytokines and inflammatory responsive proteins in hypothalamus. This phenomenon is accompanied by increased activation of c-Jun N-terminal kinase and nuclear factor-kappaB. In addition, HL feeding leads to impaired functional and molecular activation of the insulin-signaling pathway, which is paralleled by increased serine phosphorylation of the insulin receptor and insulin receptor substrate-2. Intracerebroventricular treatment of HL rats with a specific inhibitor of c-Jun N-terminal kinase (SP600125) restores insulin signaling and leads to a reduced caloric intake and weight loss. We conclude that HL feeding induces a local proinflammatory status in the hypothalamus, which results in impaired anorexigenic insulin signaling.

Cross-talk between the insulin and leptin signaling systems in rat hypothalamus.

OBJECTIVE: To investigate whether insulin and leptin share common intracellular signal transduction pathways and to determine whether these hormonal signaling systems modulate each other's action in rat hypothalamus. RESEARCH METHODS AND PROCEDURES: Male Wistar rats were studied after chronic implantation of an intracerebroventricular catheter into the third ventricle. Immunoprecipitation and immunoblotting were used to examine the activation of insulin and leptin signaling molecules in the rat hypothalamus. RESULTS: Insulin alone is able to produce molecular activation of insulin receptor substrates (IRSs)/phosphatidylinositol 3-kinase (PI 3-kinase)/Akt and mitogen-activated protein (MAP) kinase signaling pathways in hypothalamus, whereas leptin alone activates MAP kinase and IRSs/PI 3-kinase signaling with no effect on Akt. Combined infusion of leptin and insulin provokes a dual action. There was no quantitative potentialization of any single hormone's action on the elements of the insulin signaling pathway, IRSs/PI 3-kinase/Akt, and MAP kinase. Conversely, leptin plus insulin leads to quantitative potentialization of molecular signaling through the Janus kinase/signal transducer and activator of transcription pathway. DISCUSSION: We provide evidence for a convergence of leptin and insulin signaling at the level of IRSs-PI 3-kinase and a divergence at the level of Akt. Moreover, our results indicate a direct and positive cross-talk between insulin and leptin at the level of Janus kinase 2 and signal transducer and activator of transcription 3 tyrosine phosphorylation. This mechanism may serve to potentiate the activity of both insulin and leptin pathways and to increase stimulation in physiological processes such as the control of food intake and body weight, which are under the combined control of insulin and leptin.