Calcitonin Gene-Related Peptide-Induced Phosphorylation of STAT3 in Arcuate Neurons Is a Link in the Metabolic Benefits of Portal Glucose.

INTRODUCTION: Intestinal gluconeogenesis (IGN) exerts metabolic benefits in energy homeostasis via the neural sensing of portal glucose. OBJECTIVE: The aim of this work was to determine central mechanisms involved in the effects of IGN on the control of energy homeostasis. METHODS: We investigated the effects of glucose infusion into the portal vein, at a rate that mimics IGN, in conscious wild-type, leptin-deficient Ob/Ob and calcitonin gene-related peptide (CGRP)-deficient mice. RESULTS: We report that portal glucose infusion decreases food intake and plasma glucose and induces in the hypothalamic arcuate nucleus (ARC) the phosphorylation of STAT3, the classic intracellular messenger of leptin signaling. This notably takes place in POMC-expressing neurons. STAT3 phosphorylation does not require leptin, since portal glucose effects are observed in leptin-deficient Ob/Ob mice. We hypothesized that the portal glucose effects could require CGRP, a neuromediator previously suggested to suppress hunger. In line with this hypothesis, neither the metabolic benefits nor the phosphorylation of STAT3 in the ARC take place upon portal glucose infusion in CGRP-deficient mice. Moreover, intracerebroventricular injection of CGRP activates hypothalamic phosphorylation of STAT3 in mice, and CGRP does the same in hypothalamic cells. Finally, no metabolic benefit of dietary fibers (known to depend on the induction of IGN), takes place in CGRP-deficient mice. CONCLUSIONS: CGRP-induced phosphorylation of STAT3 in the ARC is part of the neural chain determining the hunger-modulating and glucose-lowering effects of IGN/portal glucose.

Combined effect of plant sterols and dietary fiber for the treatment of hypercholesterolemia.

Hypercholesterolemia is a major contributor for disease burden in both the developed and developing world and an important risk factor for cardiovascular diseases (CVD). Phytosterols (PhS) and dietary fiber (DF) act as low density lipoprotein cholesterol (LDL-C) lowering agents, offering an effective treatment against high blood cholesterol and CVD. The aim of this review was to consider clinical evidence that analyzed the combination of PhS and DF in a cereal carrier for lowering LDL-C. Electronic database searches were carried out to identify peer-reviewed journal articles, from which five intervention studies that combined both components in a cereal carrier were identified and included in the present review. LDL-C lowering effects varied widely among studies, due to large heterogeneity in study design, subject baseline characteristics, length of the interventions, PhS and DF dosage and type of DF used. In relation to a time of intake, three studies suggested a frequency or distribution of the product's consumption during the day, while two studies did not consider this factor. Overall, the selected studies found significant differences on LDL-C concentrations, although not all of them reached the expected outcomes. Future research should be conducted to explore the effect that different types of DF exert on LDL-C when combined with PhS, and to analyze the effect of the product's time of intake in order to suggest an optimal moment of the day for its consumption.

Central anorexigenic actions of bile acids are mediated by TGR5.

Bile acids (BAs) are signalling molecules that mediate various cellular responses in both physiological and pathological processes. Several studies report that BAs can be detected in the brain1, yet their physiological role in the central nervous system is still largely unknown. Here we show that postprandial BAs can reach the brain and activate a negative-feedback loop controlling satiety in response to physiological feeding via TGR5, a G-protein-coupled receptor activated by multiple conjugated and unconjugated BAs2 and an established regulator of peripheral metabolism3-8. Notably, peripheral or central administration of a BA mix or a TGR5-specific BA mimetic (INT-777) exerted an anorexigenic effect in wild-type mice, while whole-body, neuron-specific or agouti-related peptide neuronal TGR5 deletion caused a significant increase in food intake. Accordingly, orexigenic peptide expression and secretion were reduced after short-term TGR5 activation. In vitro studies demonstrated that activation of the Rho-ROCK-actin-remodelling pathway decreases orexigenic agouti-related peptide/neuropeptide Y (AgRP/NPY) release in a TGR5-dependent manner. Taken together, these data identify a signalling cascade by which BAs exert acute effects at the transition between fasting and feeding and prime the switch towards satiety, unveiling a previously unrecognized role of physiological feedback mediated by BAs in the central nervous system.

Hypothalamic bile acid-TGR5 signaling protects from obesity.

Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet-induced obesity.

Inhibiting Microglia Expansion Prevents Diet-Induced Hypothalamic and Peripheral Inflammation.

Cell proliferation and neuroinflammation in the adult hypothalamus may contribute to the pathogenesis of obesity. We tested whether the intertwining of these two processes plays a role in the metabolic changes caused by 3 weeks of a high-saturated fat diet (HFD) consumption. Compared with chow-fed mice, HFD-fed mice had a rapid increase in body weight and fat mass and specifically showed an increased number of microglia in the arcuate nucleus (ARC) of the hypothalamus. Microglia expansion required the adequate presence of fats and carbohydrates in the diet because feeding mice a very high-fat, very low-carbohydrate diet did not affect cell proliferation. Blocking HFD-induced cell proliferation by central delivery of the antimitotic drug arabinofuranosyl cytidine (AraC) blunted food intake, body weight gain, and adiposity. AraC treatment completely prevented the increase in number of activated microglia in the ARC, the expression of the proinflammatory cytokine tumor necrosis factor-α in microglia, and the recruitment of the nuclear factor-κB pathway while restoring hypothalamic leptin sensitivity. Central blockade of cell proliferation also normalized circulating levels of the cytokines leptin and interleukin 1ß and decreased peritoneal proinflammatory CD86 immunoreactive macrophage number. These findings suggest that inhibition of diet-dependent microglia expansion hinders body weight gain while preventing central and peripheral inflammatory responses due to caloric overload.

Adipose tissue redistribution caused by an early consumption of a high sucrose diet in a rat model.

INTRODUCTION: Obesity is a major public health problem worldwide. The quantity and site of accumulation of adipose tissue is of great importance for the physiopathology of this disease. OBJECTIVES: The aim of this study was to assess the effect of a high carbohydrate diet on adipose tissue distribution. METHODS: Male Wistar rats, control (CONT) and high sucrose diet (HSD; 30% sucrose in their drinking water), were monitored during 24 weeks and total energy and macronutrient intake were estimated by measuring daily average consumption. A bioelectrical impedance procedure was performed at 22 weeks of treatment to assess body compartments and systolic arterial blood pressure was measured. Serum was obtained and retroperitoneal adipose tissue was collected and weighed. RESULTS: HSD ingested less pellets and beverage, consuming less lipids and proteins than CONT, but the same amount of carbohydrates. Retroperitoneal adipose tissue was more abundant in HSD. Both groups were normoglycemic; triglycerides, adiponectin and leptin levels were higher, while total cholesterol and HDL-cholesterol were lower in HSD; insulin, HOMA index and systolic blood pressure had a tendency of being higher in HSD. DISCUSSION: This model presents dyslipidemia and a strong tendency for insulin resistance and hypertension. Even though there was no difference in body compartments between groups, retroperitoneal adipose tissue was significantly increased in HSD. This suggests that a rearrangement of adipose tissue distribution towards the abdominal cavity takes place as a result of chronic high sucrose consumption, which contributes to a higher risk of suffering from metabolic and chronic degenerative diseases.

Introducción: la obesidad es uno de los mayores problemas de salud pública en todo el mundo. El momento en que se establecee, la distribución y cantidad de tejido adiposo son de gran importancia para comprender su fisiopatología. Objetivos: observar la distribución de tejido adiposo en una dieta alta en sacarosa desde una edad temprana en un modelo animal. Métodos: se utilizaron ratas Wistar recién destetadas, animales control (CONT; agua ad libitum) y animales con dieta alta en sacarosa (HSD; 30% de sacarosa en el agua) durante 24 semanas. Se calcularon las kilocalorías y macronutrientes ingeridos diariamente; se evaluaron por impedancia bioeléctrica los compartimientos corporales, se midió la presión sistólica, se obtuvo el tejido adiposo retroperitoneal y el suero para medir parámetros bioquímicos. Resultados: los animales HSD comieron y bebieron menos, obteniendo menos proteínas y lípidos, sin diferencia en los hidratos de carbono. El tejido adiposo fue más abundante en HSD. Ambos grupos CONT Y HSD fueron normoglucémicos; HSD tuvieron triglicéridos, adiponectina y leptina altos, y el colesterol y las HDL más bajos; la insulina, el HOMA y la presión sistólica tuvieron tendencia a ser mayores en HSD. Discusión: este modelo presenta dislipidemia y una tendencia a tener resistencia a la insulina e hipertensión. A pesar de no haber una diferencia en los compartimentos corporales entre grupos, el tejido adiposo tuvo una localización específica en la espalda y fue más abundante en HSD. En conclusión, la distribución de grasa en el abdomen es consecuencia de una ingestión crónica alta en sacarosa, lo que predispone a padecer enfermedades crónico-degenerativas.

A genetic variant of the CAPN10 gene in Mexican subjects with dyslipidemia is associated with increased HDL-cholesterol concentrations after the consumption of a soy protein and soluble fiber dietary portfolio.

Dyslipidemia is a major public health problem, and therefore, it is important to develop dietary strategies to diminish the prevalence of this disorder. It was recently reported that diet may play an important role in triggering insulin resistance by interacting with genetic variants at the CAPN10 gene locus in patients with metabolic syndrome. Nonetheless, it remains unknown whether genetic variants of genes involved in the development of type 2 diabetes are associated with variations in high-density lipoprotein cholesterol (HDL-C). The study used a single-center, prospective, cohort design. Here, we assessed the effect of four variants of the CAPN10 gene on HDL-C levels in response to a soy protein and soluble fiber dietary portfolio in subjects with dyslipidemia. In 31 Mexican dyslipidemic individuals, we analyzed four CAPN10 gene variants (rs5030952, rs2975762, rs3792267, and rs2975760) associated with type 2 diabetes. Subjects with the GG genotype of the rs2975762 variant of the CAPN10 gene were better responders to dietary intervention, showing increased HDL-C concentrations from the first month of treatment. HDL-C concentrations in participants with the wild type genotype increased by 17.0%, whereas the HDL-C concentration in subjects with the variant genotypes increased by only 3.22% (p = 0.03); the low-density lipoprotein cholesterol levels of GG carriers tended to decrease (-12.6%). These results indicate that Mexican dyslipidemic carriers of the rs2975762-GG genotype are better responders to this dietary intervention.

Dyslipidemia is a major public health problem, and therefore, it is important to develop dietary strategies to diminish the prevalence of this disorder. It was recently reported that diet may play an important role in triggering insulin resistance by interacting with genetic variants at the CAPN10 gene locus in patients with metabolic syndrome. Nonetheless, it remains unknown whether genetic variants of genes involved in the development of type 2 diabetes are associated with variations in high-density lipoprotein cholesterol (HDL-C). The study used a single-center, prospective, cohort design. Here, we assessed the effect of four variants of the CAPN10 gene on HDL-C levels in response to a soy protein and soluble fiber dietary portfolio in subjects with dyslipidemia. In 31 Mexican dyslipidemic individuals, we analyzed four CAPN10 gene variants (rs5030952, rs2975762, rs3792267, and rs2975760) associated with type 2 diabetes. Subjects with the GG genotype of the rs2975762 variant of the CAPN10 gene were better responders to dietary intervention, showing increased HDL-C concentrations from the first month of treatment. HDL-C concentrations in participants with the wild type genotype increased by 17.0%, whereas the HDL-C concentration in subjects with the variant genotypes increased by only 3.22% (p = 0.03); the low-density lipoprotein cholesterol levels of GG carriers tended to decrease (-12.6%). These results indicate that Mexican dyslipidemic carriers of the rs2975762-GG genotype are better responders to this dietary intervention.

Adipose tissue redistribution caused by an early consumption of a high sucrose diet in a rat model / Redistribución del tejido adiposo en un modelo de rata debido al alto consumo de sacarosa desde edad temprana

Introduction: obesity is a major public health problem worldwide. The quantity and site of accumulation of adipose tissue is of great importance for the physiopathology of this disease. Objectives: the aim of this study was to assess the effect of a high carbohydrate diet on adipose tissue distribution. Methods: male Wistar rats, control (CONT) and high sucrose diet (HSD; 30% sucrose in their drinking water), were monitored during 24 weeks and total energy and macronutrient intake were estimated by measuring daily average consumption. A bioelectrical impedance procedure was performed at 22 weeks of treatment to assess body compartments and systolic arterial blood pressure was measured. Serum was obtained and retroperitoneal adipose tissue was collected and weighed. Results: HSD ingested less pellets and beverage, consuming less lipids and proteins than CONT, but the same amount of carbohydrates. Retroperitoneal adipose tissue was more abundant in HSD. Both groups were normoglycemic; triglycerides, adiponectin and leptin levels were higher, while total cholesterol and HDLcholesterol were lower in HSD; insulin, HOMA index and systolic blood pressure had a tendency of being higher in HSD. Discussion: this model presents dyslipidemia and a strong tendency for insulin resistance and hypertension. Even though there was no difference in body compartments between groups, retroperitoneal adipose tissue was significantly increased in HSD. This suggests that a rearrangement of adipose tissue distribution towards the abdominal cavity takes place as a result of chronic high sucrose consumption, which contributes to a higher risk of suffering from metabolic and chronic degenerative diseases (AU)

Introducción: la obesidad es uno de los mayores problemas de salud pública en todo el mundo. El momento en que se establece, la distribución y cantidad de tejido adiposo son de gran importancia para comprender su fisiopatología. Objetivos: observar la distribución de tejido adiposo en una dieta alta en sacarosa desde una edad temprana en un modelo animal. Métodos: se utilizaron ratas Wistar recién destetadas, animales control (CONT; agua ad libitum) y animales con dieta alta en sacarosa (HSD; 30% de sacarosa en el agua) durante 24 semanas. Se calcularon las kilocalorías y macronutrientes ingeridos diariamente; se evaluaron por impedancia bioeléctrica los compartimientos corporales, se midió la presión sistólica, se obtuvo el tejido adiposo retroperitoneal y el suero para medir parámetros bioquímicos. Resultados: los animales HSD comieron y bebieron menos, obteniendo menos proteínas y lípidos, sin diferencia en los hidratos de carbono. El tejido adiposo fue más abundante en HSD. Ambos grupos CONT Y HSD fueron normoglucémicos; HSD tuvieron triglicéridos, adiponectina y leptina altos, y el colesterol y las HDL más bajos; la insulina, el HOMA y la presión sistólica tuvieron tendencia a ser mayores en HSD. Discusión: este modelo presenta dislipidemia y una tendencia a tener resistencia a la insulina e hipertensión. A pesar de no haber una diferencia en los compartimentos corporales entre grupos, el tejido adiposo tuvo una localización específica en la espalda y fue más abundante en HSD. En conclusión, la distribución de grasa en el abdomen es consecuencia de una ingestión crónica alta en sacarosa, lo que predispone a padecer enfermedades crónico-degenerativas (AU)

A genetic variant of the CAPN10 gene in Mexican subjects with dyslipidemia is associated with increased HDL-cholesterol concentrations after the consumption of a soy protein and soluble fiber dietary portfolio / Una variante genética del gen capn10 en sujetos mexicanos con dislipidemia se asocia con un aumento de las concentraciones de colesterol hdl después del consumo de un portafolio dietario de soya y fibra soluble

Dyslipidemia is a major public health problem, and therefore, it is important to develop dietary strategies to diminish the prevalence of this disorder. It was recently reported that diet may play an important role in triggering insulin resistance by interacting with genetic variants at the CAPN10 gene locus in patients with metabolic syndrome. Nonetheless, it remains unknown whether genetic variants of genes involved in the development of type 2 diabetes are associated with variations in high-density lipoprotein cholesterol (HDL-C). The study used a single-center, prospective, cohort design. Here, we assessed the effect of four variants of the CAPN10 gene on HDL-C levels in response to a soy protein and soluble fiber dietary portfolio in subjects with dyslipidemia. In 31 Mexican dyslipidemic individuals, we analyzed four CAPN10 gene variants (rs5030952, rs2975762, rs3792267, and rs2975760) associated with type 2 diabetes. Subjects with the GG genotype of the rs2975762 variant of the CAPN10 gene were better responders to dietary intervention, showing increased HDL-C concentrations from the first month of treatment. HDL-C concentrations in participants with the wild type genotype increased by 17.0%, whereas the HDL-C concentration in subjects with the variant genotypes increased by only 3.22% (p = 0.03); the low-density lipoprotein cholesterol levels of GG carriers tended to decrease (-12.6%). These results indicate that Mexican dyslipidemic carriers of the rs2975762-GG genotype are better responders to this dietary intervention (AU)

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