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.

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.

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.

Without visual guidance, patients with Parkinson disease had more difficulty in perceiving the extent of a movement made to a target away from the body, a task requiring reliance on proprioceptive feedback. Parkinsonian patients had no more difficulty than controls in making movements to a target on the surface of the body when they could use tactile sensations. Movement difficulties in patients with Parkinson disease may relate in part to a decrease in proprioception. Activities that enhance kinesthetic awareness may be an important adjunct to the treatment of these patients.

No abstract

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 LRb3 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.

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.

The analgesic actions of opioids are in large part mediated by activation of brainstem pain modulating neurons that depress nociceptive transmission at the level of the dorsal horn. The present study was designed to characterize the contribution of N-methyl-D-aspartate (NMDA)- and non-NMDA-mediated excitatory transmission within the rostral ventromedial medulla (RVM) to the activation of brainstem inhibitory output neurons and analgesia produced by systemic morphine administration. The NMDA receptor antagonist D-2-amino-5-phosophonopentanoic acid (AP5), the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX) or saline was infused into the RVM of lightly anesthetized rats while recording the activity of identified pain modulating neurons: 'off-cells', thought to inhibit nociceptive transmission, and 'on-cells', thought to facilitate nociception. Nociceptive responsiveness (tail flick latency) was not affected by either antagonist. AP5, but not CNQX, attenuated or blocked activation and disinhibition of off-cells and the antinociception produced by systemically administered morphine. Reflex-related discharge of on-cells was unaffected by AP5, but significantly attenuated by CNQX. The present results highlight two important aspects of RVM pain modulatory circuits. First, morphine given systemically produces its analgesic effect at least in part by recruiting an NMDA-mediated excitatory process to activate off-cells within the RVM. This excitatory process may play a role in the analgesic synergy produced by simultaneous mu-opioid activation at different levels of the neuraxis. Second, reflex-related activation of on-cells is mediated by a non-NMDA receptor, and this activation does not appear to play a significant role in regulating reflex responses to acute noxious stimuli. Excitatory amino acid-mediated excitation thus has at least two distinct roles within the RVM, activating off-cells and on-cells under different conditions.