Neuronal control of energy homeostasis

Neuronal control of body energy homeostasis is the key mechanism by which animals and humans regulate their long-term energy balance. Various hypothalamic neuronal circuits (which include the hypothalamic melanocortin, midbrain dopamine reward and caudal brainstem autonomic feeding systems) control energy intake and expenditure to maintain body weight within a narrow range for long periods of a life span. Numerous peripheral metabolic hormones and nutrients target these structures providing feedback signals that modify the default "settings" of neuronal activity to accomplish this balance. A number of molecular genetic tools for manipulating individual components of brain energy homeostatic machineries, in combination with anatomical, electrophysiological, pharmacological and behavioral techniques, have been developed, which provide a means for elucidating the complex molecular and cellular mechanisms of feeding behavior and metabolism. This review will highlight some of these advancements and focus on the neuronal circuitries of energy homeostasis.     

Gender differences in the control of energy homeostasis

The world is experiencing an epidemic of obesity and its concomitant health problems. One implication is that the normally robust negative feedback system that controls energy homeostasis must be responding to different inputs than in the past. In this review we discuss the influence of gender on the efficacy of adiposity hormones as they interact with food intake control systems in the brain. Specifically, the levels of insulin and leptin in the blood are correlated with body fat, insulin being related mainly to visceral fat and leptin to subcutaneous fat. Since females carry more fat subcutaneously and males carry more fat viscerally, leptin correlates better with total body fat in females and insulin correlates better in males. High visceral fat and plasma insulin are also risk factors for the complications of obesity, including type-2 diabetes, cardiovascular problems, and certain cancers, and these are more prevalent in males. Consistent with these systemic differences, the brains of females are more sensitive to the catabolic actions of low doses of leptin whereas the brains of males are more sensitive to the catabolic action of low doses of insulin. The implications of this are discussed.     

Endocannabinoids control the induction of cerebellar LTD

The long-term depression (LTD) of parallel fiber (PF) synapses onto Purkinje cells plays a central role in motor learning. Endocannabinoid release and LTD induction both depend upon activation of the metabotropic glutamate receptor mGluR1, require postsynaptic calcium increases, are synapse specific, and have a similar dependence on the associative activation of PF and climbing fiber synapses. These similarities suggest that endocannabinoid release could account for many features of cerebellar LTD. Here we show that LTD induction is blocked by a cannabinoid receptor (CB1R) antagonist, by inhibiting the synthesis of the endocannabinoid 2-arachidonyl glycerol (2-AG), and is absent in mice lacking the CB1R. Although CB1Rs are prominently expressed presynaptically at PF synapses, LTD is expressed postsynaptically. In contrast, a previously described transient form of inhibition mediated by endocannabinoids is expressed presynaptically. This indicates that Purkinje cells release 2-AG that activates CB1Rs to both transiently inhibit release and induce a postsynaptic form of LTD.     

Completing the loop: neuron-adipocyte interactions and the control of energy homeostasis.

Control of energy homeostasis requires communication between the brain and adipose tissue. The sympathetic nervous system plays an integral role in relaying information during this process. Recent investigations indicate that the contributions of the sympathetic nervous system to the regulation of adipose tissue are greater than initially appreciated. A recently developed co-culture system provides evidence that a local feedback loop may exist between sympathetic neurons and adipose tissue. The co-culture approach may prove useful in further investigations of the interaction between sympathetic neurons and adipocytes, and might be adapted to study interactions between other types of neurons and adipose tissue.     

The role of estrogen receptors in the control of energy and glucose homeostasis

Estrogens have been related to energy balance and glucose metabolism for a long time; however, the mechanisms involved in their actions are now being unveiled. The development of ERalpha and ERbeta knockout mice has demonstrated the participation of these receptors in the regulation of many processes related to the control of energy homeostasis. These include food intake and energy expenditure, insulin sensitivity in the liver and muscle, adipocyte growth and its body distribution as well as the pancreatic beta-cell function. In addition, other membrane receptors unrelated to ERalpha and ERbeta function in key tissues involved in energy balance and glucose homeostasis, i.e. the islet of Langerhans and the hypothalamus. Along with naturally occurring estrogens, there are endocrine disrupters that act as environmental estrogens and can impair the physiological action of ERalpha, ERbeta and other membrane ERs. New research is revealing a link between environmental estrogenic pollutants and the metabolic syndrome.     

A putative physiological role of hypothalamic CNTF in the control of energy homeostasis

Administration of CNTF durably reduces food intake and body weight in obese humans and rodent models. However, the involvement of endogenous CNTF in the central regulation of energy homeostasis needs to be elucidated. Here, we demonstrate that CNTF and its receptor are expressed in the arcuate nucleus, a key hypothalamic region controlling food intake, and that CNTF levels are inversely correlated to body weight in rats fed a high-sucrose diet. Thus endogenous CNTF may act, in some individuals, as a protective factor against weight gain during hypercaloric diet and could account for individual differences in the susceptibility to obesity.     

Endocannabinoids and the gut

In the digestive tract, there is evidence for the presence of high amounts of endocannabinoids (anandamide and 2-arachidonylglycerol) and of mechanisms for endocannabinoid metabolism and possibly endocannabinoid uptake. Pharmacological studies have shown that anandamide inhibits excitatory transmission and peristalsis in the isolated guinea-pig ileum and reduces intestinal motility in the mouse in vivo; all these effects are mediated by CB(1) receptors, which are located on enteric nerves. Conversely, the selective CB(1) receptor antagonist SR141716A increased intestinal motility and this effect is likely due to the displacement of endocannabinoids rather than to its inverse agonist properties. Interestingly, inhibitory effects of anandamide via non-CB(1) receptors and stimulatory effects via vanilloid receptors have also been proposed.     

Role for insulin signaling in catecholaminergic neurons in control of energy homeostasis

Dopaminergic midbrain neurons integrate signals on food palatability and food-associated reward into the complex control of energy homeostasis. To define the role of insulin receptor (IR) signaling in this circuitry, we inactivated IR signaling in tyrosine hydroxylase (Th)-expressing cells of mice (IR(ΔTh)). IR inactivation in Th-expressing cells of mice resulted in increased body weight, increased fat mass, and hyperphagia. While insulin acutely stimulated firing frequency in 50% of dopaminergic VTA/SN neurons, this response was abolished in IR(ΔTh) mice. Moreover, these mice exhibited an altered response to cocaine under food-restricted conditions. Taken together, these data provide in?vivo evidence for a critical role of insulin signaling in catecholaminergic neurons to control food intake and energy homeostasis.     

Endocannabinoids in neuroendopsychology: multiphasic control of mitochondrial function

The endocannabinoid system (ECS) is a construct based on the discovery of receptors that are modulated by the plant compound tetrahydrocannabinol and the subsequent identification of a family of nascent ligands, the ‘endocannabinoids’. The function of the ECS is thus defined by modulation of these receptors—in particular, by two of the best-described ligands (2-arachidonyl glycerol and anandamide), and by their metabolic pathways. Endocannabinoids are released by cell stress, and promote both cell survival and death according to concentration. The ECS appears to shift the immune system towards a type 2 response, while maintaining a positive energy balance and reducing anxiety. It may therefore be important in resolution of injury and inflammation. Data suggest that the ECS could potentially modulate mitochondrial function by several different pathways; this may help explain its actions in the central nervous system. Dose-related control of mitochondrial function could therefore provide an insight into its role in health and disease, and why it might have its own pathology, and possibly, new therapeutic directions.     

Endocannabinoids control spasticity in a multiple sclerosis model.

Spasticity is a complicating sign in multiple sclerosis that also develops in a model of chronic relapsing experimental autoimmune encephalomyelitis (CREAE) in mice. In areas associated with nerve damage, increased levels of the endocannabinoids, anandamide (arachidonoylethanolamide, AEA) and 2-arachidonoyl glycerol (2-AG), and of the AEA congener, palmitoylethanolamide (PEA), were detected here, whereas comparable levels of these compounds were found in normal and non-spastic CREAE mice. While exogenously administered endocannabinoids and PEA ameliorate spasticity, selective inhibitors of endocannabinoid re-uptake and hydrolysis-probably through the enhancement of endogenous levels of AEA, and, possibly, 2-arachidonoyl glycerol-significantly ameliorated spasticity to an extent comparable with that observed previously with potent cannabinoid receptor agonists. These studies provide definitive evidence for the tonic control of spasticity by the endocannabinoid system and open new horizons to therapy of multiple sclerosis, and other neuromuscular diseases, based on agents modulating endocannabinoid levels and action, which exhibit little psychotropic activity.     

Endocannabinoids and liver disease. I. Endocannabinoids and their receptors in the liver

Cannabinoid receptors (CB1 and CB2) and their endogenous ligands (endocannabinoids) have recently emerged as novel mediators of liver diseases. Endogenous activation of CB1 receptors promotes nonalcoholic fatty liver disease (NAFLD) and progression of liver fibrosis associated with chronic liver injury; in addition, CB1 receptors contribute to the pathogenesis of portal hypertension and cirrhotic cardiomyopathy. CB2 receptor-dependent effects are also increasingly characterized, including antifibrogenic effects and regulation of liver inflammation during ischemia-reperfusion and NAFLD. It is likely that the next few years will allow us to delineate whether molecules targeting CB1 and CB2 receptors are useful therapeutic agents for the treatment of chronic liver diseases.     

Brain circuits regulating energy homeostasis

Recent years have seen an impetus in the study for central mechanisms regulating energy balance, and caloric intake possibly as a response to the obesity pandemic. This renewed interest as well as drastic improvements in the tools that are now currently available to neuroscientists, has yielded a great deal of insight into the mechanisms by which the brain regulates metabolic function, and volitional aspects of feeding in response to metabolic signals like leptin, insulin and ghrelin. Among these mechanisms are the complex intracellular signals elicited by these hormones in neurons. Moreover, these signals produce and modulate the metabolism of the cell at the level of the mitochondria. Finally, these signals promote plastic changes that alter the synaptic circuitry in a number of circuits and ultimately affect cellular, physiological and behavioral responses in defense of energy homeostasis. These mechanisms are surveyed in this review.     

The molecular genetics of the melanocortin pathway and energy homeostasis

The CNS melanocortin pathway plays an important role in the control of body weight. Two papers in this issue of Cell Metabolism, Lee et al., 2006 and Biebermann et al., 2006, suggest that beta MSH--a product of POMC processing--plays an unanticipated role in this pathway in humans.     

Adiponectin and energy homeostasis: consensus and controversy

Adiponectin regulates energy homeostasis through the modulation of glucose and fatty acid metabolism in peripheral tissues. However, its central effect on energy balance remains unclear and controversial. Despite the disparate data, recent advances in our understanding of the signal transduction mechanisms used by adiponectin in the periphery and in the hypothalamus suggest that intracellular cross-talk between adiponectin, leptin and insulin may occur at several levels. The present review will summarize recent reports describing the peripheral and central effects of adiponectin and discuss progress concerning its molecular mechanisms. We will also particularly focus on apparent controversies and related mechanisms associated with the central effects of adiponectin on energy homeostasis.     

AMPK: a nutrient and energy sensor that maintains energy homeostasis

AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. Once activated by falling energy status, it promotes ATP production by increasing the activity or expression of proteins involved in catabolism while conserving ATP by switching off biosynthetic pathways. AMPK also regulates metabolic energy balance at the whole-body level. For example, it mediates the effects of agents acting on the hypothalamus that promote feeding and entrains circadian rhythms of metabolism and feeding behaviour. Finally, recent studies reveal that AMPK conserves ATP levels through the regulation of processes other than metabolism, such as the cell cycle and neuronal membrane excitability.     

Endocannabinoids and liver disease. II. Endocannabinoids in the pathogenesis and treatment of liver fibrosis

Hepatic fibrosis is the response of the liver to chronic injury and is associated with portal hypertension, progression to hepatic cirrhosis, liver failure, and high incidence of hepatocellular carcinoma. On a molecular level, a large number of signaling pathways have been shown to contribute to the activation of fibrogenic cell types and the subsequent accumulation of extracellular matrix in the liver. Recent evidence suggests that the endocannabinoid system is an important part of this complex signaling network. In the injured liver, the endocannabinoid system is upregulated both at the level of endocannabinoids and at the endocannabinoid receptors CB1 and CB2. The hepatic endocannabinoid system mediates both pro- and antifibrogenic effects by activating distinct signaling pathways that differentially affect proliferation and death of fibrogenic cell types. Here we will summarize current findings on the role of the hepatic endocannabinoid system in liver fibrosis and discuss emerging options for its therapeutic exploitation.