RESUMO

Most known types of nonsyndromic monogenic obesity are caused by rare mutations in genes of the leptin-melanocortin pathway controlling appetite and adiposity. In contrast, congenital generalized lipodystrophy represents the most extreme form of leanness in humans caused by recessive mutations in four genes involved in phospholipid/triglyceride synthesis and lipid droplet/caveolae structure. In this disease, the inability to store triglyceride in adipocytes results in hypoleptinemia and ectopic hepatic and muscle fat accumulation leading to fatty liver, hypertriglyceridemia and severe insulin resistance. As a result of hypoleptinemia, patients with lipodystrophy show alterations in eating behaviour characterized by constant increased energy intake. As it occurs in obesity caused by genetic leptin deficiency, exogenous leptin rapidly reduces hunger scores in patients with congenital generalized lipodystrophy, with additional beneficial effects on glucose homeostasis and metabolic profile normalization. The melanocortin-4 receptor agonist setmelanotide has been used in the treatment of monogenic obesities. There is only one report on the effect of setmelanotide in a patient with partial lipodystrophy resulting in mild reductions in hunger scores, with no improvements in metabolic status. The assessment of contrasting phenotypes of obesity/leanness represents an adequate strategy to understand the pathophysiology and altered eating behaviour associated with adipose tissue excessive accumulation/paucity.

Assuntos

Adiposidade , Comportamento Alimentar , Lipodistrofia Generalizada Congênita , Obesidade , Humanos , Leptina , Lipodistrofia Generalizada Congênita/genética , Obesidade/genética , Fenótipo

RESUMO

Obesity and cholesterol gallstone disease (GSD) are frequently coexisting diseases; therefore and considering the current worldwide obesity epidemics, a precise understanding of the pathophysiological relationships between GSD and insulin resistance (IR) is important. Classically, obesity has been understood as a risk factor for GSD and the gallbladder (GB) viewed as a simple bile reservoir, with no metabolic roles whatsoever. However, consistent evidence has showed that both GSD and cholecystectomy associates with fatty liver and IR, raising the possibility that the GB is indeed an organ with metabolic regulatory roles. Herein, we review the pathophysiological mechanisms by which GSD, IR, and obesity are interconnected, with emphasis in the actions of the GB as a regulator of bile acids kinetics and a hormone secreting organ, with metabolic actions at the systemic level. We also examine the relationships between increased hepatic lipogenic in IR states and GSD pathogenesis. We propose a model in which GSD and hepatic IR mutually interact to determine a state of dysregulated lipid and energy metabolism that potentiate the metabolic dysregulation of obesity.

Assuntos

Colelitíase/complicações , Colelitíase/fisiopatologia , Resistência à Insulina/fisiologia , Obesidade/complicações , Obesidade/fisiopatologia , Tecido Adiposo/fisiopatologia , Animais , Ácidos e Sais Biliares/metabolismo , Colecistectomia/estatística & dados numéricos , Metabolismo Energético/fisiologia , Fígado Gorduroso/complicações , Fígado Gorduroso/fisiopatologia , Feminino , Vesícula Biliar/fisiopatologia , Humanos , Intestinos/fisiopatologia , Metabolismo dos Lipídeos/fisiologia , Fígado/fisiopatologia , Fatores de Risco

RESUMO

BACKGROUND/OBJECTIVES: Abdominal obesity (AO) is associated with elevated risk for cardiovascular diseases; however, this association is less clear for non-obese people. We estimated the association of AO and cardiovascular risk factors (CVRF) and disease in non-obese adult individuals from Chile. SUBJECTS/METHODS: 5248 adults (15 years of age or older) of both sexes from the Chilean National Health Survey (October 2009 -September 2010, response rate 85%.) were included. Information on myocardial infarction and stroke was self-reported. BMI, waist circumference (WC), arterial pressure, plasma glucose, and cholesterol levels were measured. Predictive accuracy of WC was evaluated by area under curve of receiver operating characteristic analysis and cut off points were established by Youden Index. Relationship between AO and CVRF was analyzed by Chi-squared tests. RESULTS: Normal weight/overweight/obesity were present in 34.4%/45.2%/18.1% of men and 33.4%/33.6%/27.5% of women. Predictive accuracy of WC to identify at least one CVRF was 0.70/0.67 and optimal cutoff points for WC in non-obese subjects were 91/83 cm in men/women, respectively. AO was present in 98.2%/99.1% of obese, 70.5%/77.4% of overweight and 12.4%/16.4% of normal weight men/women. AO was associated with increased frequency of CVRF in overweight men (6/8 and stroke) and women (4/8) and higher frequency in normal weight men (8/8 and myocardial infarction/stroke) and women (6/8 and myocardial infarction). CONCLUSIONS: WC cutoff points calculated for non-obese chilean population discriminate more differences in CVRF in normal weight woman. AO significantly increases the frequency of CVRF and diseases in overweight and especially normal weight individuals. WC can be used as a low cost, feasible and reproducible predictor for CVRF in non-obese individuals in most clinical settings.

Assuntos

Doenças Cardiovasculares/etiologia , Obesidade Abdominal/complicações , Sobrepeso/complicações , Adulto , Área Sob a Curva , Glicemia/análise , Índice de Massa Corporal , Chile , Colesterol/sangue , Estudos Transversais , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Obesidade Abdominal/diagnóstico , Sobrepeso/diagnóstico , Curva ROC , Fatores de Risco , Circunferência da Cintura

RESUMO

The discovery of metabolically active brown adipose tissue (BAT) in adult humans has fuelled the research of diverse aspects of this previously neglected tissue. BAT is solely present in mammals and its clearest physiological role is non-shivering thermogenesis, owing to the capacity of brown adipocytes to dissipate metabolic energy as heat. Recently, a number of other possible functions have been proposed, including direct regulation of glucose and lipid homeostasis and the secretion of a number of factors with diverse regulatory actions. Herein, we review recent advances in general biological knowledge of BAT and discuss the possible implications of this tissue in human metabolic health. In particular, we confront the claimed thermogenic potential of BAT for human energy balance and body mass regulation, mostly based on animal studies, with the most recent quantifications of human BAT.

Assuntos

Tecido Adiposo Marrom/fisiologia , Obesidade/patologia , Animais , Humanos , Obesidade/metabolismo , Obesidade/prevenção & controle

RESUMO

AIMS: Pancreatic ß-cells synthesize and release serotonin (5 hydroxytryptamine, 5HT); however, the role of 5HT receptors on glucose stimulated insulin secretion (GSIS) and the mechanisms mediating this function is not fully understood. The aims of this study were to determine the expression profile of 5HT receptors in murine MIN6 ß-cells and to examine the effects of pharmacological activation of 5HT receptor Htr2b on GSIS and mitochondrial function. MATERIALS AND METHODS: mRNA levels of 5HT receptors in MIN6 cells were quantified by RT qPCR. GSIS was assessed in MIN6 cells in response to global serotonergic activation with 5HT and pharmacological Htr2b activation or inhibition with BW723C86 or SB204741, respectively. In response to Htr2b activation also was evaluated the mRNA and protein levels of PGC1α and PPARy by RT-qPCR and western blotting and mitochondrial function by oxygen consumption rate (OCR) and ATP cellular content. RESULTS: We found that mRNA levels of most 5HT receptors were either very low or undetectable in MIN6 cells. By contrast, Htr2b mRNA was present at moderate levels in these cells. Preincubation (6 h) of MIN6 cells with 5HT or BW723C86 reduced GSIS and the effect of 5HT was prevented by SB204741. Preincubation with BW723C86 increased PGC1α and PPARy mRNA and protein levels and decreased mitochondrial respiration and ATP content in MIN6 cells. CONCLUSIONS: Our results indicate that prolonged Htr2b activation in murine ß-cells decreases glucose-stimulated insulin secretion and mitochondrial activity by mechanisms likely dependent on enhanced PGC1α/PPARy expression.

Assuntos

Insulina/metabolismo , PPAR gama/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Receptores de Serotonina/genética , Serotonina/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Humanos , Indóis/farmacologia , Insulina/genética , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Consumo de Oxigênio/genética , PPAR gama/biossíntese , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/biossíntese , Receptores de Serotonina/biossíntese , Serotonina/genética , Serotonina/farmacologia , Tiofenos/farmacologia , Ureia/análogos & derivados , Ureia/farmacologia

RESUMO

AIMS: Mutations in 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) result in lipodystrophy, insulin resistance and diabetes. Autophagy is required for normal adipogenesis and adipose tissue development. The aim of this study was to determine whether impaired autophagy or excessive cell death underlie the adipogenic inability of Agpat2(-/-) mice preadipocytes. METHODS: Preadipocytes were isolated from interscapular brown adipose tissue (BAT) of Agpat2(-/-) and Agpat2(+/+) newborn mice and cultured/differentiated in vitro. Intracellular lipids were quantified by oil red O staining. Cell death was assessed by lactate dehydrogenase (LDH) activity. Apoptosis and autophagy regulatory factors were determined at the mRNA and protein level with Real-time PCR, immunoblot and immunofluorescence. RESULTS: Adipogenically induced Agpat2(-/-) preadipocytes had fewer lipid-loaded cells and lower levels of adipocyte markers than wild type preadipocytes. Before adipogenic differentiation, autophagy-related proteins (ATGs) ATG3, ATG5-ATG12 complex, ATG7 and LC3II were increased but autophagic flux was reduced, as suggested by increased p62 levels, in Agpat2(-/-) preadipocytes. Adipogenic induction increased LDH levels in the culture media in Agpat2(-/-) preadipocytes but no differences were observed in the activation of Caspase 3 or in markers of autophagic flux. CONCLUSIONS: AGPAT2 is required for in vitro adipogenesis of mouse preadipocytes. Autophagy defects or apoptosis are not involved in the adipogenic failure of Agpat2(-/-) preadipocytes.

Assuntos

Aciltransferases/deficiência , Adipócitos Marrons/citologia , Adipócitos Marrons/enzimologia , Adipogenia/fisiologia , Aciltransferases/genética , Adipogenia/genética , Animais , Apoptose , Autofagia , Diferenciação Celular , Células Cultivadas , Metabolismo dos Lipídeos , Camundongos , Camundongos Knockout , Células-Tronco/citologia , Células-Tronco/metabolismo

RESUMO

The adipose tissue is an endocrine organ that produces a variety of protein hormones. One of them is leptin, which regulates several critical functions at the central nervous system such as caloric intake, basal energy expenditure, reproduction, glucose and lipid metabolism and osteogenesis. Acting at a local level, leptin modulates the immune system and promotes liver fibrogenesis. The most promising therapeutic implications of leptin will possibly be in type 1 diabetes mellitus (DM1). Its supplementation in animal models of DM1 prevents hyperglycemia and ketoacidosis. These actions depend on the activation of leptin receptors in the central nervous system and the suppression of glucagon signaling in the liver.

Assuntos

Leptina/fisiologia , Tecido Adiposo/fisiologia , Animais , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/terapia , Metabolismo Energético/fisiologia , Humanos , Leptina/uso terapêutico , Camundongos , Ratos , Receptores para Leptina/fisiologia

RESUMO

The adipose tissue is an endocrine organ that produces a variety of protein hormones. One of them is leptin, which regulates several critical functions at the central nervous system such as caloric intake, basal energy expenditure, reproduction, glucose and lipid metabolism and osteogenesis. Acting at a local level, leptin modulates the immune system and promotes liver fibrogenesis. The most promising therapeutic implications of leptin will possibly be in type 1 diabetes mellitus (DM1). Its supplementation in animal models of DM1 prevents hyperglycemia and ketoacidosis. These actions depend on the activation of leptin receptors in the central nervous system and the suppression of glucagon signaling in the liver.

Assuntos

Animais , Humanos , Camundongos , Ratos , Leptina/fisiologia , Tecido Adiposo/fisiologia , Diabetes Mellitus Tipo 1/terapia , /terapia , Metabolismo Energético/fisiologia , Leptina/uso terapêutico , Receptores para Leptina/fisiologia

RESUMO

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by extreme reduction of white adipose tissue (WAT) mass. CGL type 1 is the most frequent form and is caused by mutations in AGPAT2. Genetic and clinical studies were performed in two affected sisters of a Chilean family. These patients have notoriously dissimilar metabolic abnormalities that correlate with differential levels of circulating leptin and soluble leptin receptor fraction. Sequencing of AGPAT2 exons and exon-intron boundaries revealed two homozygous mutations in both sisters. Missense mutation c.299G>A changes a conserved serine in the acyltransferase NHX4D motif of AGPAT2 (p.Ser100Asn). Intronic c.493-1G>C mutation destroy a conserved splicing site that likely leads to exon 4 skipping and deletion of whole AGPAT2 substrate binding domain. In silico protein modeling provided insights of the mechanisms of lack of catalytic activity owing to both mutations.

Assuntos

Aciltransferases/genética , Predisposição Genética para Doença/genética , Lipodistrofia Generalizada Congênita/genética , Mutação , Irmãos , Aciltransferases/química , Aciltransferases/metabolismo , Adulto , Sequência de Bases , Análise Mutacional de DNA , Feminino , Homozigoto , Humanos , Leptina/sangue , Leptina/metabolismo , Lipodistrofia Generalizada Congênita/sangue , Lipodistrofia Generalizada Congênita/metabolismo , Modelos Moleculares , Fenótipo , Estrutura Terciária de Proteína , Receptores para Leptina/metabolismo

RESUMO

Cholesterol has evolved to fulfill sophisticated biophysical, cell signaling and endocrine requirements of animal systems. At a cellular level, cholesterol is found in membranes, where it increases both bilayer stiffness and impermeability to water and ions. Furthermore, cholesterol is integrated into specialized lipid-protein membrane microdomains with critical topographical and signaling functions. At an organismal level, cholesterol is the precursor for all steroid hormones, including gluco- and mineralo-corticoids, sex hormones and vitamin D, all of which regulate carbohydrate, sodium, reproductive and bone homeostasis, respectively. This sterol is also the precursor for bile acids, which are important for intestinal absorption of dietary lipids as well as energy and glucose metabolic regulation. Importantly, complex mechanisms maintain cholesterol within physiological ranges and the disregulation of these mechanisms results in embryonic or adult diseases, caused by either excessive or reduced tissue cholesterol levels. The causative role of cholesterol in these diseases has been demonstrated by diverse genetic and pharmacologic animal models that are commented in this review.

Assuntos

Colesterol/fisiologia , Aterosclerose/fisiopatologia , Transporte Biológico , Colesterol/biossíntese , Colesterol/metabolismo , Desenvolvimento Fetal/fisiologia , Humanos

RESUMO

Cholesterol has evolved to fulfill sophisticated biophysical, cell signalling, and endocrine functions in animal systems. At the cellular level, cholesterol is found in membranes where it increases both bilayer stiffness and impermeability to water and ions. Furthermore, cholesterol is integrated into specialized lipid-protein membrane microdomains with critical topographical and signalling functions. At the organismal level, cholesterol is the precursor of all steroid hormones, including gluco- and mineralo-corticoids, sex hormones, and vitamin D, which regulate carbohydrate, sodium, reproductive, and bone homeostasis, respectively. This sterol is also the immediate precursor of bile acids, which are important for intestinal absorption of dietary lipids as well as energy homeostasis and glucose regulation. Complex mechanisms maintain cholesterol within physiological ranges and the dysregulation of these mechanisms results in embryonic or adult diseases, caused by either excessive or reduced tissue cholesterol levels. The causative role of cholesterol in these conditions has been demonstrated by genetic and pharmacological manipulations in animal models of human disease that are discussed herein. Importantly, the understanding of basic aspects of cholesterol biology has led to the development of high-impact pharmaceutical therapies during the past century. The continuing effort to offer successful treatments for prevalent cholesterol-related diseases, such as atherosclerosis and neurodegenerative disorders, warrants further interdisciplinary research in the coming decades.