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

Nitric Oxide Released From Luminal S-nitroso-n-acetylcysteine Increases Gastric Mucosal Blood Flow

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Nitric oxide (NO)-mediated vasodilation plays a key role in gastric mucosal defense, and NO-donor drugs may protect against diseases associated with gastric mucosal blood flow (GMBF) deficiencies. In this study, we used the ex vivo gastric chamber method and Laser Doppler Flowmetry to characterize the effects of luminal aqueous NO-donor drug S-nitroso-N-acetylcysteine (SNAC) solution administration compared to aqueous NaNO2 and NaNO3 solutions (pH 7.4) on GMBF in Sprague-Dawley rats. SNAC solutions (600 mu M and 12 mM) led to a rapid threefold increase in GMBF, which was maintained during the incubation of the solutions with the gastric mucosa, while NaNO2 or NaNO3 solutions (12 mM) did not affect GMBF. SNAC solutions (600 mu M and 12 mM) spontaneously released NO at 37 degrees C at a constant rate of 0.3 or 14 nmol center dot mL(-1)center dot min(-1), respectively, while NaNO2 (12 mM) released NO at a rate of 0.06 nmol center dot mL(-1)center dot min(-1) and NaNO3 (12 mM) did not release NO. These results suggest that the SNAC-induced GMBF increase is due to their higher rates of spontaneous NO release compared to equimolar NaNO2 solutions. Taken together, our data indicate that oral SNAC administration is a potential approach for gastric acid-peptic disorder prevention and treatment.20341094123Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2011/50514-5, 2013/07173-8]CNPq [309390/2011-7]FAPESP [2008/57560-0

Unmanipulated Native Fat Exposed To High-energy Diet, But Not Autologous Grafted Fat By Itself, May Lead To Overexpression Of Ki67 And Pai-1

Background: Although its unclear oncological risk, which led to more than 20 years of prohibition of its use, fat grafting to the breast is widely used nowadays even for aesthetic purposes. Thus, we proposed an experimental model in rats to analyze the inflammatory activity, cellular proliferation and levels of Plasminogen Activator Inhibitor (PAI-1) in grafted fat, and in native fat exposed to high-energy diet in order to study the oncological potential of fat tissue. Methods: Samples of grafted fat of rats on regular-energy diet were compared with paired samples of native fat from the same rat on regular-energy diet and on high-energy diet in a different time. Analysis involved microscopic comparisons using hematoxylin-eosin staining, immunohistochemistry with anti-CD68-labelled macrophages, and gene expression of Ki-67 and PAI-1. Results: Hematoxylin-eosin staining analyses did not find any atypical cellular infiltration or unusual tissue types in the samples of grafted fat. The inflammatory status, assessed through immunohistochemical identification of CD68-labelled macrophages, was similar among samples of native fat and grafted fat of rat on regular-energy diet and of native fat of rats on high-energy diet. Real-time PCR revealed that high-energy diet, but not fat grafting, leads to proliferative status on adipose tissue (overexpression of ki-67, p = 0.046) and raised its PAI-1 levels, p < 0.001. Conclusion: While the native adipose tissue overexpressed PAI-1 and KI67 when exposed to high-energy diet, the grafted fat by itself was unable to induce cellular proliferation, chronic inflammatory activity and/or elevation of PAI-1 levels.

Robust Control for Dynamical Systems With Non-Gaussian Noise via Formal Abstractions

Controllers for dynamical systems that operate in safety-critical settings must account for stochastic disturbances. Such disturbances are often modeled as process noise in a dynamical system, and common assumptions are that the underlying distributions are known and/or Gaussian. In practice, however, these assumptions may be unrealistic and can lead to poor approximations of the true noise distribution. We present a novel controller synthesis method that does not rely on any explicit representation of the noise distributions. In particular, we address the problem of computing a controller that provides probabilistic guarantees on safely reaching a target, while also avoiding unsafe regions of the state space. First, we abstract the continuous control system into a finite-state model that captures noise by probabilistic transitions between discrete states. As a key contribution, we adapt tools from the scenario approach to compute probably approximately correct (PAC) bounds on these transition probabilities, based on a finite number of samples of the noise. We capture these bounds in the transition probability intervals of a so-called interval Markov decision process (iMDP). This iMDP is, with a user-specified confidence probability, robust against uncertainty in the transition probabilities, and the tightness of the probability intervals can be controlled through the number of samples. We use state-of-the-art verification techniques to provide guarantees on the iMDP and compute a controller for which these guarantees carry over to the original control system. In addition, we develop a tailored computational scheme that reduces the complexity of the synthesis of these guarantees on the iMDP. Benchmarks on realistic control systems show the practical applicability of our method, even when the iMDP has hundreds of millions of transitions.Comment: To appear in the Journal of Artificial Intelligence Research (JAIR). arXiv admin note: text overlap with arXiv:2110.1266

(-)-tarchonanthuslactone Exerts A Blood Glucose-increasing Effect In Experimental Type 2 Diabetes Mellitus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)A number of studies have proposed an anti-diabetic effect for tarchonanthuslactone based on its structural similarity with caffeic acid, a compound known for its blood glucose-reducing properties. However, the actual effect of tarchonanthuslactone on blood glucose level has never been tested. Here, we report that, in opposition to the common sense, tarchonanthuslactone has a glucose-increasing effect in a mouse model of obesity and type 2 diabetes mellitus. The effect is acute and non-cumulative and is present only in diabetic mice. In lean, glucose-tolerant mice, despite a slight increase in blood glucose levels, the effect was not significant.20350385049Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Institute of Chemistry/UNICAMPFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [proc. 13/07607-8]FAPESP [11/50514-5, 12/09254-2, 10/08673-6, 2009/53606-8

[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

Saturated Fatty Acids Modulate Autophagy's Proteins In The Hypothalamus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Autophagy is an important process that regulates cellular homeostasis by degrading dysfunctional proteins, organelles and lipids. In this study, the hypothesis that obesity could lead to impairment in hypothalamic autophagy in mice was evaluated by examining the hypothalamic distribution and content of autophagic proteins in animal with obesity induced by 8 or 16 weeks high fat diet to induce obesity and in response to intracerebroventricular injections of palmitic acid. The results showed that chronic exposure to a high fat diet leads to an increased expression of inflammatory markers and downregulation of autophagic proteins. In obese mice, autophagic induction leads to the downregulation of proteins, such as JNK and Bax, which are involved in the stress pathways. In neuron cell-line, palmitate has a direct effect on autophagy even without inflammatory activity. Understanding the cellular and molecular bases of overnutrition is essential for identifying new diagnostic and therapeutic targets for obesity.103Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2011/14565-4, RA 2011/51205-6

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