Neuroendokrynna regulacja masy ciała: integracja tkanki tłuszczowej, układu pokarmowego i mózgu

Human body weight is maintained at a fairly stable level regardless of changes in energy intake and energy expenditure. Compensatory mechanisms within the central nervous system (CNS), which regulate food intake and energy expenditure, are triggered by other central and peripheral signals. Peripherally, the main sources of those signals are the adipose tissue, gastrointestinal tract, and pancreas. The main signal originating from the adipose tissue is leptin, which promotes the activation of anorexigenic pathways in the CNS. Similarly, the central action of insulin also reduces food intake and stimulates catabolic pathways. The gastrointestinal tract contributes with several peptides that influence food intake, such as ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), oxyntomodulin (OXM), and cholecystokinin (CCK). Other substances secreted by the pancreas, such as pancreatic polypeptide (PP) and amylin, a hormone co-secreted with insulin, also affect energy balance. More recently, the endocannabinoid system has also been identified as a contributor in the maintenance of energy balance. Better understanding of these mechanistic systems involved in the regulation of energy metabolism will hopefully lead to the development of new therapeutic approaches against obesity, metabolic syndrome, and other nutritional disorders. (Pol J Endocrinol 2010; 61 (2): 194-206)Masa ciała człowieka jest utrzymywana na względnie stałym poziomie niezależnie od zmian zarówno w dostarczaniu energii, jak i jej zużywania. Mechanizm kompensacyjny w ośrodkowym układzie nerwowym (CNS, central nervous system [OUN]), który reguluje przyjmowanie pokarmu i wydatek energii jest uruchamiany przez inne sygnały ośrodkowe i obwodowe. Obwodowo, źródłem tych sygnałów jest tkanka tłuszczowa, układ pokarmowy i trzustka. Głównym sygnałem pochodzącym z tkanki tuszczowej jest leptyna, która powoduje aktywację anoreksogennych dróg przekazu sygnału w CNS. Podobnie, oddziaływanie ośrodkowe insuliny także zmniejsza przyjmowanie pokarmu i stymuluje kataboliczne drogi przekazu sygnału. W układzie pokarmowym współdziała kilka peptydów, które wpływają na przyjmowanie pokarmu, takie jak grelina, peptyd podobny do glukagonu (GLP-1, glucagon-like peptide), peptyd YY (PYY, peptide YY), oksyntomodulina (OXM, oxyntomodulin) i cholecystokinina (CCK, cholecystokinin), Pozostałe substancje wydzielane przez trzustkę, takie jak polipeptyd trzustkowy (PP, pancreatic polypeptide) i amylina, hormon wydzielany jednocześnie z insuliną , także wpływają na równowagę energetyczną. W najnowszych badaniach stwierdzono, że układ endokannabinoidowy przyczynia sie do zachowania równowagi energetycznej. Lepsze zrozumienie mechanizmów układów wpływających na regulacje przemiany energii przyczyni się do rozwoju nowych terapii otyłości, zespołu metabolicznego i innych zaburzeń odżywiania. (Endokrynol Pol 2010; 61 (2): 194-206

[hypothalamic Dysfunction In Obesity].

Obesity, defined as abnormal or excessive fat accumulation that may impair life quality, is one of the major public health problems worldwide. It results from an imbalance between food intake and energy expenditure. The control of energy balance in animals and humans is performed by the central nervous system (CNS) by means of neuroendocrine connections, in which circulating peripheral hormones, such as leptin and insulin, provide signals to specialized neurons of the hypothalamus reflecting body fat stores, and induce appropriate responses to maintain the stability of these stores. The majority of obesity cases are associated with central resistance to both leptin and insulin actions. In experimental animals, high-fat diets can induce an inflammatory process in the hypothalamus, which impairs leptin and insulin intracellular signaling pathways, and results in hyperphagia, decreased energy expenditure and, ultimately, obesity. Recent evidence obtained from neuroimaging studies and assessment of inflammatory markers in the cerebrospinal fluid of obese subjects suggests that similar alterations may be also present in humans. In this review, we briefly present the mechanisms involved with the loss of homeostatic control of energy balance in animal models of obesity, and the current evidence of hypothalamic dysfunction in obese humans.56341-5

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.2019COORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPSem informação2013/07607-

Central role of obesity in endothelial cell dysfunction and cardiovascular risk

Atherosclerosis is the leading cause of mortality in the contemporary world. The critical role of the endothelial cells (EC) in vascular homeostasis, the metabolic changes that take place when the cell is activated, and the elements involved in these processes have been widely explored over the past years. Obesity and its impact, promoting a rise in blood levels of free fatty acids (FAs) are often associated with atherosclerosis and cardiovascular mortality. However, the mechanisms that promote cardiovascular structural changes and adaptive changes in the ECs, particularly in the context of obesity, are little known. Here, we reviewed studies that assessed the metabolic adaptations of healthy and dysfunctional ECs during exposure to FAs, as well as the epidemiological perspectives of cardiovascular structural changes in obesity. Finally, we explored the role of new agents - sphingolipids, dietary unsaturated fatty acids and sodium-glucose cotransporter-2 inhibitors (iSGLT2) - in atherosclerosis and their relationship with obesity.651879

Insulin signalling in heart involves insulin receptor substrates-1 and - 2, activation of phosphatidylinositol 3-kinase and the JAK 2-growth related pathway

Objective: Hyperinsulinemia is a common feature of obesity and hypertension and may be associated with abnormal metabolism and growth of heart muscle and vascular wall. Most of the known actions of insulin were characterised in muscle, adipose tissue and liver. In this study we investigate the initial steps of insulin signalling in rat heart. Methods: After insulin infusion in the cava vein of male Wistar rats, the insulin receptor, insulin receptor substrates-1 and -2, phosphatidylinositol 3- kinase activity and Janus kinase (JAK) 2 engagement were studied by immunoprecipitation and immunoblot of heart extracts. Results: An insulin load induces rapid autophosphorylation of the insulin receptor which is followed by the phosphorylation of insulin receptor substrates-1 and -2. The phosphorylation of these early intracellular substrates leads to the association of the p85 subunit of phosphatidylinositol 3-kinase and subsequent activation of its catalytic p110 subunit. Besides activation of the lipid metabolising enzyme phosphatidylinositol 3-kinase, the phosphorylation of insulin receptor substrates-1 and -2 engages the intracellular kinase JAK 2 and induces JAK 2-STAT 1 complex formation. Conclusion: We demonstrate that the early steps of insulin signalling in heart include the phosphorylation-activation of the insulin receptor, engagement of insulin receptor substrates-1 and -2 with the consequent activation of phosphatidylinositol 3-kinase and the involvement of the recently discovered growth related pathway-JAK 2-STAT 1

Hypothalamic Inhibition Of Acetyl-coa Carboxylase Stimulates Hepatic Counter-regulatory Response Independent Of Ampk Activation In Rats.

Hypothalamic AMPK acts as a cell energy sensor and can modulate food intake, glucose homeostasis, and fatty acid biosynthesis. Intrahypothalamic fatty acid injection is known to suppress liver glucose production, mainly by activation of hypothalamic ATP-sensitive potassium (K(ATP)) channels. Since all models employed seem to involve malonyl-CoA biosynthesis, we hypothesized that acetyl-CoA carboxylase can modulate the counter-regulatory response independent of nutrient availability. In this study employing immunoblot, real-time PCR, ELISA, and biochemical measurements, we showed that reduction of the hypothalamic expression of acetyl-CoA carboxylase by antisense oligonucleotide after intraventricular injection increased food intake and NPY mRNA, and diminished the expression of CART, CRH, and TRH mRNA. Additionally, as in fasted rats, in antisense oligonucleotide-treated rats, serum glucagon and ketone bodies increased, while the levels of serum insulin and hepatic glycogen diminished. The reduction of hypothalamic acetyl-CoA carboxylase also increased PEPCK expression, AMPK phosphorylation, and glucose production in the liver. Interestingly, these effects were observed without modification of hypothalamic AMPK phosphorylation. Hypothalamic ACC inhibition can activate hepatic counter-regulatory response independent of hypothalamic AMPK activation.8e6266

Novel fibrin-fibronectin matrix accelerates mice skin wound healing

Plasma fibrinogen (F1) and fibronectin (pFN) polymerize to form a fibrin clot that is both a hemostatic and provisional matrix for wound healing. About 90% of plasma F1 has a homodimeric pair of γ chains (γγF1), and 10% has a heterodimeric pair of γ and more acidic γ′ chains (γγ′F1). We have synthesized a novel fibrin matrix exclusively from a 1:1 (molar ratio) complex of γγ′F1 and pFN in the presence of highly active thrombin and recombinant Factor XIII (rFXIIIa). In this matrix, the fibrin nanofibers were decorated with pFN nanoclusters (termed γγ′F1:pFN fibrin). In contrast, fibrin made from 1:1 mixture of γγF1 and pFN formed a sporadic dis- tribution of “pFN droplets” (termed γγF1+pFN fibrin). The γγ′F1:pFN fibrin enhanced the adhesion of primary human umbilical vein endothelium cells (HUVECs) relative to the γγF1+FN fibrin. Three dimensional (3D) culturing showed that the γγ′F1:pFN complex fibrin matrix enhanced the proliferation of both HUVECs and primary human fibroblasts. HUVECs in the 3D γγ′F1:pFN fibrin exhibited a starkly enhanced vascular mor- phogenesis while an apoptotic growth profile was observed in the γγF1+pFN fibrin. Relative to γγF1+pFN fibrin, mouse dermal wounds that were sealed by γγ′F1:pFN fibrin exhibited accelerated and enhanced healing. This study suggests that a 3D pFN presentation on a fibrin matrix promotes wound healing

The partial inhibition of hypothalamic IRX3 exacerbates obesity

The Iroquois homeobox 3 (Irx3) gene has been identified as a functional long-range target of obesity-associated variants within the fat mass and obesity-associated protein (FTO) gene. It is highly expressed in the hypothalamus, and both whole-body knockout and hypothalamic restricted abrogation of its expression results in a lean phenotype, which is mostly explained by the resulting increased energy expenditure in the brown adipose tissue. Because of its potential implication in the pathogenesis of obesity, we evaluated the hypothalamic cell distribution of Irx3 and the outcomes of inhibiting its expression in a rodent model of diet-induced obesity. Methods: Bioinformatics tools were used to evaluate the correlations between hypothalamic Irx3 and neurotransmitters, markers of thermogenesis and obesity related phenotypes. Droplet-sequencing analysis in >20,000 hypothalamic cells was used to explore the types of hypothalamic cells expressing Irx3. Lentivirus was used to inhibit hypothalamic Irx3 and the resulting phenotype was studied. Findings: IRX3 is expressed predominantly in POMC neurons. Its expression is inhibited during prolonged fasting, as well as when mice are fed a high-fat diet. The partial inhibition of hypothalamic Irx3 using a lentivirus resulted in increased diet-induced body mass gain and adiposity due to increased caloric intake and reduced energy expenditure. Interpretation: Contrary to the results obtained when lean mice are submitted to complete inhibition of Irx3, partial inhibition of hypothalamic Irx3 in obese mice causes an exacerbation of the obese phenotype. These data suggest that at least some of the Irx3 functions in the hypothalamus are regulated according to a hormetic pattern, and modulation of its expression can be a novel approach to modifying the body's energy-handling regulation.39448460FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2013/07607-8; 2017/02983-

Brown fat triglyceride content is associated with cardiovascular risk markers in adults from a tropical region

Brown adipose tissue (BAT) is regarded as an interesting potential target for the treatment of obesity, diabetes, and cardiovascular diseases, and the detailed characterization of its structural and functional phenotype could enable an advance in these fields. Most studies evaluating BAT structure and function were performed in temperate climate regions, and we are yet to know how these findings apply to the 40% of the world's population living in tropical areas. Here, we used F-18-fluorodeoxyglucose positron emission tomography - magnetic resonance imaging to evaluate BAT in 45 lean, overweight, and obese volunteers living in a tropical area in Southeast Brazil. We aimed at investigating the associations between BAT activity, volume, metabolic activity, and BAT content of triglycerides with adiposity and cardiovascular risk markers in a sample of adults living in a tropical area and we showed that BAT glucose uptake is not correlated with leanness; instead, BAT triglyceride content is correlated with visceral adiposity and markers of cardiovascular risk. This study expands knowledge regarding the structure and function of BAT in people living in tropical areas. In addition, we provide evidence that BAT triglyceride content could be an interesting marker of cardiovascular risk