Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus

Abstract

The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.

17α‐estradiol acts through hypothalamic pro‐opiomelanocortin expressing neurons to reduce feeding behavior

“…Pomc ‐expressing neurons located within the ARC constitute the dominant anorexigenic node of appetite regulating neurons and are viewed as key regulators of energy homeostasis. Activation of these neurons via peripheral appetite regulators such as leptin (Cowley et al., 2001) and insulin (Benoit et al., 2002) promotes satiety and diminishes food intake. Given our previous observation that 17α‐E2 treatment increased hypothalamic transcripts of the melanocortin system (Stout et al., 2017), we reasoned that 17α‐E2 might promote satiety in HFD fed mice through Pomc ‐expressing neurons.…”

Body weight is regulated by the brain: a link between feeding and emotion

“…61 The arcuate nucleus: a site of leptin action Evidence indicates that leptin directly acts on the arcuate nucleus of the hypothalamus (Arc; Figure 1): (i) Radiolabeled leptin binds highly to the mediobasal hypothalamic region involving the Arc; 62 (ii) cells expressing Ob-Rb mRNA populate in the Arc and several other brain sites; [57][58][59][60][61] (iii) leptin induces the expression of an immediate early gene, c-fos (a marker of neuronal activation) [63][64][65][66] and suppressor of cytokine signaling-3 (SOCS-3, a cellular marker of direct leptin action) [65][66][67] in the Arc; (iv) Arc cells are directly hyperpolarized and depolarized by leptin. 68,69 The central melanocortin system mediates leptin action The term 'melanocortin' indicates a series of peptides that are cleaved from pro-opiomelanocortin (POMC). 70 One of the POMC products, adrenocorticotropic hormone, is secreted by the anterior pituitary and stimulates adrenocortical cells.…”

“…[74][75][76] Finally, leptin directly depolarizes POMC neurons. 69 Of importance, a-MSH acts as an agonist for the melanocortin-4 receptor (MC4-R), 70,77,78 a Gs-proteincoupled receptor distributed in the CNS. 35,79,80 The MC4-R is an established regulator of food intake and body weight, and blockade of this receptor causes obesity.…”

“…149,150 Importantly, NPY-producing Arc neurons coexpress AgRP and are inhibited by leptin. 66,68,69,97,98 Of NPY receptor subtypes, the Y1-, (Y1-R), Y2-, and Y5-receptors have been implicated in the regulation ), with permission). h: GFP-producing cell labeling the MC4-R. Bar ¼ 10 mm.…”

“…Needless to say, GABA is also important not only in cortico-subcortical circuits but also in subcortical circuits. 24 It is notable that GABA plays a role in regulating key hypothalamic circuits, as illustrated by Cowley et al, 69 and van den Pol et al 134 Clearly, neuropeptides have received much attention in the field of obesity research. However, the regulation of hypothalamic synaptic activity critical for coordinated food intake and body weight likely relies on the action of amino-acid transmitters including glutamate and GABA.…”