Hypothalamic inhibition of acetyl-CoA carboxylase stimulates hepatic counter-regulatory response independent of AMPK activation in rats.

Background: 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.

Fructose-induced hypothalamic AMPK activation stimulates hepatic PEPCK and gluconeogenesis due to increased corticosterone levels.

Fructose consumption causes insulin resistance and favors hepatic gluconeogenesis through mechanisms that are not completely understood. Recent studies demonstrated that the activation of hypothalamic 5'-AMP-activated protein kinase (AMPK) controls dynamic fluctuations in hepatic glucose production. Thus, the present study was designed to investigate whether hypothalamic AMPK activation by fructose would mediate increased gluconeogenesis.

Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver.

Defective liver gluconeogenesis is the main mechanism leading to fasting hyperglycemia in type 2 diabetes, and, in concert with steatosis, it is the hallmark of hepatic insulin resistance. Experimental obesity results, at least in part, from hypothalamic inflammation, which leads to leptin resistance and defective regulation of energy homeostasis. Pharmacological or genetic disruption of hypothalamic inflammation restores leptin sensitivity and reduces adiposity.

Hypothalamic action of glutamate leads to body mass reduction through a mechanism partially dependent on JAK2.

Glutamate acts in the hypothalamus promoting region-, and cell-dependent effects on feeding. Part of these effects are mediated by NMDA receptors, which are up regulated in conditions known to promote increased food intake and thermogenesis, such as exposure to cold and consumption of highly caloric diets. Here, we hypothesized that at least part of the effect of glutamate on hypothalamic control of energy homeostasis would depend on the control of neurotransmitter expression and JAK2 signaling.

Taurine enhances the anorexigenic effects of insulin in the hypothalamus of rats.

Taurine is known to modulate a number of metabolic parameters such as insulin secretion and action and blood cholesterol levels. Recent data have suggested that taurine can also reduce body adiposity in C. elegans and in rodents.

Maternal high-fat feeding through pregnancy and lactation predisposes mouse offspring to molecular insulin resistance and fatty liver.

The exposure to an increased supply of nutrients before birth may contribute to offspring obesity. Offspring from obese dams that chronically consume a high-fat diet present clinical features of metabolic syndrome, liver lipid accumulation and activation of c-Jun N-terminal kinases (JNK) consistent with the development of nonalcoholic fatty liver disease (NAFLD). However, in spite of the importance of the resistance to insulin for the development of NAFLD, the molecular alterations in the liver of adult offspring of obese dams are yet to be investigated.

Deletion of tumor necrosis factor-alpha receptor 1 (TNFR1) protects against diet-induced obesity by means of increased thermogenesis.

In diet-induced obesity, hypothalamic and systemic inflammatory factors trigger intracellular mechanisms that lead to resistance to the main adipostatic hormones, leptin and insulin. Tumor necrosis factor-alpha (TNF-alpha) is one of the main inflammatory factors produced during this process and its mechanistic role as an inducer of leptin and insulin resistance has been widely investigated. Most of TNF-alpha inflammatory signals are delivered by TNF receptor 1 (R1); however, the role played by this receptor in the context of obesity-associated inflammation is not completely known.

The role of proliferator-activated receptor gamma coactivator-1alpha in the fatty-acid-dependent transcriptional control of interleukin-10 in hepatic cells of rodents.

Interleukin-10 (IL-10) is an endogenous factor that restrains hepatic insulin resistance in diet-induced steatosis. Reducing IL-10 expression increases proinflammatory activity in the steatotic liver and worsens insulin resistance. As the transcriptional coactivator proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) plays a central role in dysfunctional hepatocytic activity in diet-induced steatosis, we hypothesized that at least part of the action of PGC-1alpha could be mediated by reducing the transcription of the IL-10 gene.

Central leptin action improves skeletal muscle AKT, AMPK, and PGC1 alpha activation by hypothalamic PI3K-dependent mechanism.

Central leptin action requires PI3K activity to modulate glucose homeostasis and peripheral metabolism. However, the mechanism behind this phenomenon is not clearly understood. We hypothesize that hypothalamic PI3K activity is important for the modulation of the AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) pathway, PGC1 alpha, and AKT in skeletal muscle (SM).

High-fat diet induces apoptosis of hypothalamic neurons.

Consumption of dietary fats is amongst the most important environmental factors leading to obesity. In rodents, the consumption of fat-rich diets blunts leptin and insulin anorexigenic signaling in the hypothalamus by a mechanism dependent on the in situ activation of inflammation. Since inflammatory signal transduction can lead to the activation of apoptotic signaling pathways, we evaluated the effect of high-fat feeding on the induction of apoptosis of hypothalamic cells.

Intracerebroventricular injection of citrate inhibits hypothalamic AMPK and modulates feeding behavior and peripheral insulin signaling.

We hypothesized that citrate might modulate the AMP-activated protein kinase/acetyl-CoA carboxylase (AMPK)/(ACC) pathway and participate in neuronal feeding control and glucose homeostasis. To address this issue, we injected citrate into the lateral ventricle of rats. Intracerebroventricular (ICV) injection of citrate diminished the phosphorylation of hypothalamic AMPK/ACC, increased the expression of anorexigenic neuropeptide (pro-opiomelanocortin and corticotropin-releasing hormone), elevated the level of malonyl-CoA in the hypothalamus, and reduced food intake.

TNF-alpha acts in the hypothalamus inhibiting food intake and increasing the respiratory quotient--effects on leptin and insulin signaling pathways.

Acting in the hypothalamus, tumor necrosis factor-alpha (TNF-alpha) produces a potent anorexigenic effect. However, the molecular mechanisms involved in this phenomenon are poorly characterized. In this study, we investigate the capacity of TNF-alpha to activate signal transduction in the hypothalamus through elements of the pathways employed by the anorexigenic hormones insulin and leptin.

Aminoguanidine prevented impairment of blood antioxidant system in insulin-dependent diabetic rats.

Non-enzymatic glycation is implicated in the development of various diseases such as Alzheimer's and diabetes mellitus. However, it is also observed during the physiologic process of aging. There is considerable interest in the contribution of oxidative stress to diabetes mellitus.

Activation of AMPK in rat hypothalamus participates in cold-induced resistance to nutrient-dependent anorexigenic signals.

The exposure of homeothermic animals to a cold environment leads to a powerful activation of orexigenic signalling which is accompanied by molecular and functional resistance to insulin-induced inhibition of feeding. Recent evidence suggests that AMPK participates in nutrient-dependent control of satiety and adiposity. The objective of the present study was to evaluate the effect of cold exposure upon the molecular activation of AMPK signalling in the hypothalamus of rats.