A. Christine Könner

MyD88 Signaling in the CNS Is Required for Development of Fatty Acid-Induced Leptin Resistance and Diet-Induced Obesity

Obesity-associated activation of inflammatory pathways represents a key step in the development of insulin resistance in peripheral organs, partially via activation of TLR4 signaling by fatty acids. Here, we demonstrate that palmitate acting in the central nervous system (CNS) inhibits leptin-induced anorexia and Stat3 activation. To determine the functional significance of TLR signaling in the CNS in the development of leptin resistance and diet-induced obesity in vivo, we have characterized mice deficient for the TLR adaptor molecule MyD88 in the CNS (MyD88(DeltaCNS)). Compared to control mice, MyD88(DeltaCNS) mice are protected from high-fat diet (HFD)-induced weight gain, from the development of HFD-induced leptin resistance, and from the induction of leptin resistance by acute central application of palmitate. Moreover, CNS-restricted MyD88 deletion protects from HFD- and icv palmitate-induced impairment of peripheral glucose metabolism. Thus, we define neuronal MyD88-dependent signaling as a key regulator of diet-induced leptin and insulin resistance in vivo.

Central insulin action regulates peripheral glucose and fat metabolism in mice

Insulin resistance is a hallmark of type 2 diabetes, and many insights into the functions of insulin have been gained through the study of mice lacking the IR. To gain a better understanding of the role of insulin action in the brain versus peripheral tissues, we created 2 mouse models with inducible IR inactivation, 1 in all tissues including brain (IRDeltawb), and 1 restricted to peripheral tissues (IRDeltaper). While downregulation of IR expression resulted in severe hyperinsulinemia in both models, hyperglycemia was more pronounced in IRDeltawb mice. Both strains displayed a dramatic upregulation of hepatic leptin receptor expression, while only IRDeltaper mice displayed increased hepatic Stat3 phosphorylation and Il6 expression. Despite a similar reduction in IR expression in white adipose tissue (WAT) mass in both models, IRDeltawb mice had a more pronounced reduction in WAT mass and severe hypoleptinemia. Leptin replacement restored hepatic Stat3 phosphorylation and normalized glucose metabolism in these mice, indicating that alterations in glucose metabolism occur largely as a consequence of lipoathrophy upon body-wide IR deletion. Moreover, chronic intracerebroventricular insulin treatment of control mice increased fat mass, fat cell size, and adipose tissue lipoprotein lipase expression, indicating that CNS insulin action promotes lipogenesis. These studies demonstrate that central insulin action plays an important role in regulating WAT mass and glucose metabolism via hepatic Stat3 activation.

Toll-like receptors: linking inflammation to metabolism

Obesity has been characterized as a state of chronic inflammation. Inflammatory signaling not only causes peripheral insulin resistance, but also promotes neuronal insulin and leptin resistance, which further propagates a positive energy balance. Upon development of obesity, numerous conditions, including increased circulating cytokine concentrations and cell autonomous dysregulation of homeostatic signaling pathways, such as the endoplasmic reticulum stress response, promote activation of stress kinases, to cause peripheral insulin as well as central insulin and leptin resistance. Recently, activation of toll-like receptor (TLR) signaling has been recognized as an alternative activator of obesity-induced inflammation. In this paper, we review recent progress in defining the molecular basis of obesity-associated TLR activation and its role in the development of metabolic syndrome.

Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b

Insulin resistance represents a hallmark during the development of type 2 diabetes mellitus and in the pathogenesis of obesity-associated disturbances of glucose and lipid metabolism. MicroRNA (miRNA)-dependent post-transcriptional gene silencing has been recognized recently to control gene expression in disease development and progression, including that of insulin-resistant type 2 diabetes. The deregulation of miRNAs miR-143 (ref. 4), miR-181 (ref. 5), and miR-103 and miR-107 (ref. 6) alters hepatic insulin sensitivity. Here we report that the expression of miR-802 is increased in the liver of two obese mouse models and obese human subjects. Inducible transgenic overexpression of miR-802 in mice causes impaired glucose tolerance and attenuates insulin sensitivity, whereas reduction of miR-802 expression improves glucose tolerance and insulin action. We identify Hnf1b (also known as Tcf2) as a target of miR-802-dependent silencing, and show that short hairpin RNA (shRNA)-mediated reduction of Hnf1b in liver causes glucose intolerance, impairs insulin signalling and promotes hepatic gluconeogenesis. In turn, hepatic overexpression of Hnf1b improves insulin sensitivity in Leprdb/db mice. Thus, this study defines a critical role for deregulated expression of miR-802 in the development of obesity-associated impairment of glucose metabolism through targeting of Hnf1b, and assigns Hnf1b an unexpected role in the control of hepatic insulin sensitivity.

Control of energy homeostasis by insulin and leptin: targeting the arcuate nucleus and beyond.

As the obesity epidemic, diabetes mellitus type 2, and associated comorbidities show no signs of abating, large efforts have been put into a better understanding of the homeostatic control mechanisms involved in regulation of body weight and energy homeostasis. For decades, the hypothalamic arcuate nucleus (ARC), which integrates peripheral signals and modulates appetite and metabolism, has been the focus of investigation. Besides these basic homeostatic circuits, food palatability and reward are thought to be major factors involved in the regulation of food intake. Highly palatable food is easily available, and is ingested even when there is no metabolic need for it. Thus, overriding of the homeostatic control systems by the cognitive, rewarding, social, and emotional aspects of palatable food may contribute to the obesity epidemic. This review aims to provide an updated view, how insulin and leptin as signals originating from the periphery of the body and communicating energy availability to the CNS act not only on ARC neurons, but also directly control the activity of neuronal circuits in control of food-associated reward mechanisms.

Selective Insulin and Leptin Resistance in Metabolic Disorders

Obesity represents a major risk factor for the development of insulin and leptin resistance, ultimately leading to a pleiotropic spectrum of metabolic alterations. However, resistance to both hormones does not uniformly affect all target cells and intracellular signaling pathways. In contrast, numerous clinical phenotypes arise from selective hormone resistance, leading to inhibition of defined intracellular signaling pathways in some tissues, while in other cell types hormone action is maintained or even overactivated. Here, we review the molecular mechanisms and clinical outcomes resulting from selective insulin and leptin resistance, which should ultimately guide future strategies for the treatment of obesity-associated diseases.

Interleukin-6 Signaling in Liver-Parenchymal Cells Suppresses Hepatic Inflammation and Improves Systemic Insulin Action

The contribution of interleukin (IL)-6 signaling in obesity-induced inflammation remains controversial. To specifically define the role of hepatic IL-6 signaling in insulin action and resistance, we have generated mice with hepatocyte-specific IL-6 receptor (IL-6R) alpha deficiency (IL-6Ralpha(L-KO) mice). These animals showed no alterations in body weight and fat content but exhibited a reduction in insulin sensitivity and glucose tolerance. Impaired glucose metabolism originated from attenuated insulin-stimulated glucose transport in skeletal muscle and fat. Surprisingly, hepatic IL-6Ralpha-disruption caused an exaggerated inflammatory response during euglycemic hyperinsulinemic clamp analysis, as revealed by increased expression of IL-6, TNF-alpha, and IL-10, as well as enhanced activation of inflammatory signaling such as phosphorylation of IkappaBalpha. Neutralization of TNF-alpha or ablation of Kupffer cells restored glucose tolerance in IL-6Ralpha(L-KO) mice. Thus, our results reveal an unexpected role for hepatic IL-6 signaling to limit hepatic inflammation and to protect from local and systemic insulin resistance.

Sensing the fuels: glucose and lipid signaling in the CNS controlling energy homeostasis.

The central nervous system (CNS) is capable of gathering information on the body’s nutritional state and it implements appropriate behavioral and metabolic responses to changes in fuel availability. This feedback signaling of peripheral tissues ensures the maintenance of energy homeostasis. The hypothalamus is a primary site of convergence and integration for these nutrient-related feedback signals, which include central and peripheral neuronal inputs as well as hormonal signals. Increasing evidence indicates that glucose and lipids are detected by specialized fuel-sensing neurons that are integrated in these hypothalamic neuronal circuits. The purpose of this review is to outline the current understanding of fuel-sensing mechanisms in the hypothalamus, to integrate the recent findings in this field, and to address the potential role of dysregulation in these pathways in the development of obesity and type 2 diabetes mellitus.

Integrative neurobiology of energy homeostasis-neurocircuits, signals and mediators

Body weight is tightly controlled in a species-specific range from insects to vertebrates and organisms have developed a complex regulatory network in order to avoid either excessive weight gain or chronic weight loss. Energy homeostasis, a term comprising all processes that aim to maintain stability of the metabolic state, requires a constant communication of the different organs involved; i.e. adipose tissue, skeletal muscle, liver, pancreas and the central nervous system (CNS). A tight hormonal network ensures rapid communication to control initiation and cessation of eating, nutrient processing and partitioning of the available energy within different organs and metabolic pathways. Moreover, recent experiments indicate that many of these homeostatic signals modulate the neural circuitry of food reward and motivation. Disturbances in each individual system can affect the maintenance and regulation of the others, making the analysis of energy homeostasis and its dysregulation highly complex. Though this cross-talk has been intensively studied for many years now, we are far from a complete understanding of how energy balance is maintained and multiple key questions remain unanswered. This review summarizes some of the latest developments in the field and focuses on the effects of leptin, insulin, and nutrient-related signals in the central regulation of feeding behavior. The integrated view, how these signals interact and the definition of functional neurocircuits in control of energy homeostasis, will ultimately help to develop new therapeutic interventions within the current obesity epidemic.

Neurocircuits integrating hormone and nutrient signaling in control of glucose metabolism

As obesity, diabetes, and associated comorbidities are on a constant rise, large efforts have been put into better understanding the cellular and molecular mechanisms by which nutrients and metabolic signals influence central and peripheral energy regulation. For decades, peripheral organs as a source and a target of such cues have been the focus of study. Their ability to integrate metabolic signals is essential for balanced energy and glucose metabolism. Only recently has the pivotal role of the central nervous system in the control of fuel partitioning been recognized. The rapidly expanding knowledge on the elucidation of molecular mechanisms and neuronal circuits involved is the focus of this review.