Feeding induced by cannabinoids is mediated independently of the melanocortin system.

BACKGROUND: Cannabinoids, the active components of marijuana, stimulate appetite, and cannabinoid receptor-1 (CB1-R) antagonists suppress appetite and promote weight loss. Little is known about how CB1-R antagonists affect the central neurocircuitry, specifically the melanocortin system that regulates energy balance. METHODOLOGY/PRINCIPAL FINDINGS: Here, we show that peripherally administered CB1-R antagonist (AM251) or agonist equally suppressed or stimulated feeding respectively in A(y) , which lack a functional melanocortin system, and wildtype mice, demonstrating that cannabinoid effects on feeding do not require melanocortin circuitry. CB1-R antagonist or agonist administered into the ventral tegmental area (VTA) equally suppressed or stimulated feeding respectively, in both genotypes. In addition, peripheral and central cannabinoid administration similarly induced c-Fos activation in brain sites suggesting mediation via motivational dopaminergic circuitry. Amperometry-detected increases in evoked dopamine (DA) release by the CB1-R antagonist in nucleus accumbens slices indicates that AM251 modulates DA release from VTA terminals. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that the effects of cannabinoids on energy balance are independent of hypothalamic melanocortin circuitry and is primarily driven by the reward system.

Regulation of central melanocortin signaling by interleukin-1 beta.

Anorexia and involuntary weight loss are common and debilitating complications of a number of chronic diseases and inflammatory states. Proinflammatory cytokines, including IL-1 beta, are hypothesized to mediate these responses through direct actions on the central nervous system. However, the neural circuits through which proinflammatory cytokines regulate food intake and energy balance remain to be characterized. Here we report that IL-1 beta activates the central melanocortin system, a key neuronal circuit in the regulation of energy homeostasis. Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) were found to express the type I IL-1 receptor. Intracerebroventricular injection of IL-1 beta induced the expression of Fos protein in ARC POMC neurons but not in POMC neurons in the commissural nucleus of the tractus solitarius. We further show that IL-1 beta increases the frequency of action potentials of ARC POMC neurons and stimulates the release of alpha-MSH from hypothalamic explants in a dose-dependent fashion. Collectively, our data support a model in which IL-1 beta increases central melanocortin signaling by activating a subpopulation of hypothalamic POMC neurons and stimulating their release of alpha-MSH.

Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons.

Despite high leptin levels, most obese humans and rodents lack responsiveness to its appetite-suppressing effects. We demonstrate that leptin modulates NPY/AgRP and alpha-MSH secretion from the ARH of lean mice. High-fat diet-induced obese (DIO) mice have normal ObRb levels and increased SOCS-3 levels, but leptin fails to modulate peptide secretion and any element of the leptin signaling cascade. Despite this leptin resistance, the melanocortin system downstream of the ARH in DIO mice is over-responsive to melanocortin agonists, probably due to upregulation of MC4R. Lastly, we show that by decreasing the fat content of the mouse's diet, leptin responsiveness of NPY/AgRP and POMC neurons recovered simultaneously, with mice regaining normal leptin sensitivity and glycemic control. These results highlight the physiological importance of leptin sensing in the melanocortin circuits and show that their loss of leptin sensing likely contributes to the pathology of leptin resistance.

Appropriate inhibition of orexigenic hypothalamic arcuate nucleus neurons independently of leptin receptor/STAT3 signaling.

Leptin directly suppresses the activity of orexigenic neurons in the hypothalamic arcuate nucleus (ARC). We examined c-Fos-like immunoreactivity (CFLIR) as a marker of ARC neuronal activity in db/db mice devoid of the signaling form of the leptin receptor (LRb) and s/s mice that express LRb(S1138) [which is defective for STAT3 (signal transducer and activator of transcription) signaling]. Both db/db and s/s animals are hyperphagic and obese. This analysis revealed that CFLIR in agouti related peptide-expressing orexigenic ARC neurons is basally elevated in db/db but not s/s mice. Consistent with these observations, electrophysiologic evaluation of a small number of neurons in s/s animals suggested that leptin appropriately suppresses the frequency of IPSCs on ARC proopiomelanocortin (POMC) neurons that are mediated by the release of GABA from orexigenic ARC neurons. CFLIR in POMC neurons of s/s mice was also increased compared with db/db animals. Thus, these data suggest that, although LRb-->STAT3 signaling is crucial for the regulation of feeding, it is not required for the acute or chronic regulation of orexigenic ARC neurons, and the activation of STAT3-mediated transcription by leptin is not required for the appropriate development of leptin responsiveness in these neurons.

Serotonin reciprocally regulates melanocortin neurons to modulate food intake.

The neural pathways through which central serotonergic systems regulate food intake and body weight remain to be fully elucidated. We report that serotonin, via action at serotonin1B receptors (5-HT1BRs), modulates the endogenous release of both agonists and antagonists of the melanocortin receptors, which are a core component of the central circuitry controlling body weight homeostasis. We also show that serotonin-induced hypophagia requires downstream activation of melanocortin 4, but not melanocortin 3, receptors. These results identify a primary mechanism underlying the serotonergic regulation of energy balance and provide an example of a centrally derived signal that reciprocally regulates melanocortin receptor agonists and antagonists in a similar manner to peripheral adiposity signals.

Hypothalamic regulatory pathways and potential obesity treatment targets.

With an ever-growing population of obese people as well as comorbidities associated with obesity, finding effective weight loss strategies is more imperative than ever. One of the challenges in curbing the obesity crisis is designing successful strategies for long-term weight loss and weight-loss maintenance. Currently, weight-loss strategies include promotion of therapeutic lifestyle changes (diet and exercise), pharmacological therapy, and bariatric surgery. This review focuses on several pharmacological targets that activate central nervous system pathways that normally limit food intake and body weight. Though it is likely that no single therapy will prove effective for everyone, this review considers several recent pre-clinical targets, and several compounds that have been in human clinical trials.

The electrophysiology of feeding circuits.

Obesity is quickly becoming one of the most common and debilitating disorders of the developed world. More than 60% of American adults are now overweight or obese, predisposing them to a host of chronic diseases. To understand the etiology of obesity, and to discover new therapies for obesity, we must understand the components of energy balance. In simple terms, energy intake (feeding) must equal energy expenditure (physical activity, basal metabolism and adaptive thermogenesis) for body weight homeostasis. To maintain homeostasis, neurocircuitry must sense both immediate nutritional status and the amount of energy stored in adipose tissue, and must be able to provide appropriate output to balance energy intake and energy expenditure. The brain receives various signals that carry information about nutritional and metabolic status including neuropeptide PYY(3-36), ghrelin, cholecystokinin, leptin, glucose and insulin. Circulating satiety signals access the brain either by "leakage" across circumventricular organs or transport across the blood-brain barrier. Signals can also activate sensory vagal terminals that innervate the whole gastrointestinal tract.

Calbindin neurons in the hamster suprachiasmatic nucleus do not exhibit a circadian variation in spontaneous firing rate.

The role of the mammalian suprachiasmatic nuclei (SCN) in generating circadian rhythms in behaviours and other physiological processes is well established. A prominent feature of SCN neurons is the circadian oscillation in action potential firing frequency, with a peak near midday. A subset of calbindin-immunoreactive (CB+) neurons form a compact subnucleus (CBsn) in the hamster SCN. Restoration of rhythmicity using fetal SCN grafts in SCN-lesioned hamsters is critically dependent upon the presence of CB+ neurons within the transplanted grafts [LeSauter & Silver (1999) J. Neurosci., 5574-5585]. The aim of the current study was to determine whether CB+ neurons within the CBsn of the hamster SCN fire action potentials in a circadian pattern as part of their output signal. Using patch-clamp recording, we demonstrated that CB+ neurons in the CBsn do not express a circadian rhythm in spontaneous firing frequency under diurnal conditions in vitro. Furthermore, the percentage of silent CB- cells varies with zeitgeber time, whereas the percentage of silent CB+ cells does not. Immunohistochemical analysis revealed that the CBsn is a nonhomogeneous nucleus, containing many more CB- than CB+ cells. Our results reveal that CB+ neurons within the CBsn represent a functionally distinct neuronal subpopulation in which rhythmic action potential output may not be necessary for the restoration of behavioural circadian rhythmicity.