POMC Neurons: From Birth to Death

Abstract

The hypothalamus is an evolutionarily conserved brain structure that regulates an organism's basic functions, such as homeostasis and reproduction. Several hypothalamic nuclei and neuronal circuits have been the focus of many studies seeking to understand their role in regulating these basic functions. Within the hypothalamic neuronal populations, the arcuate melanocortin system plays a major role in controlling homeostatic functions. The arcuate pro-opiomelanocortin (POMC) neurons in particular have been shown to be critical regulators of metabolism and reproduction because of their projections to several brain areas both in and outside of the hypothalamus, such as autonomic regions of the brain stem and spinal cord. Here, we review and discuss the current understanding of POMC neurons from their development and intracellular regulators to their physiological functions and pathological dysregulation.

Keywords: POMC; development; food intake; hypothalamus; obesity.

Figure 1

Development of POMC neurons. (a) Overview of the factors that regulate embryonic POMC development and postnatal maturation of POMC circuitry. Notch signaling, Shh, Nkx2-1, Six3, Rax and Sox2 regulate POMC neurogenesis during embryonic development. Some POMC-positive progenitors become NPY and Kisspeptin neurons. At birth, POMC neuronal projections are immature. Leptin, autophagy, and BDNF regulate POMC axon growth. In the adult stage, leptin, glucose, glucocorticoid, and HFD modulate synaptic input organization onto the POMC neurons (red, excitatory synapses; blue, inhibitory synapses; green, astrocytes). POMC neurogenesis also occurs in adulthood, and it is shown to be induced by the injections of the hNSCs and iPSCs. CNTF and HF diet affect adult POMC neurogenesis. (b) Outline of the Notch signaling pathway regulating POMC neurogenesis. The progenitor cell, via the formation of the Notch/DLL1 complex with a neighboring cell, inhibits its own differentiation to a POMC neuron (lateral inhibition) by activating the transcriptional repressor Hes1, which is induced by NICD/Rbpjk binding. Once the Notch/DLL1 is removed, Mash1 and Ngn2/3 can initiate the differentiation of the cell into a POMC neuron. Abbreviations: BDNF, brain-derived neurotrophic factor; CNTF, ciliary neurotrophic factor; E, embryonic day; HFD, high-fat diet; hNSC, hypothalamic neural stem cell; HVZ, hypothalamic ventricular zone; iPSC, inducible pluripotent stem cell; Ngn 2/3, neurogenin 2/3; NICD, intracellular domain of Notch; NPY, neuropeptide Y; NSC, neural stem cell; POMC, pro-opiomelanocortin.

Figure 2

Hormonal and nutritional regulation of POMC neurons. (a) Localization of insulin-, leptin- and serotonin-responsive POMC neurons in the ARC, modified from (49). (b) POMC protein processing and signaling pathways regulating POMC neuronal activity. Please note that the effects of insulin, leptin, and 5-HT may not occur in the same POMC cell as shown in panel a. (c) The paradoxical orexigenic effect of POMC neuronal activation in response to cannabinoids due to the release of the orexigenic POMC-derived β-endorphin. Abbreviations: 3V, third ventricle; ACTH, adrenocorticotropin; AMPK, 5’-adenosine monophosphate activating kinase; ARC, arcuate nucleus; CLIP, corticotropin-like intermediate lobe peptide; CPE, carboxypepetidase E; DMH, dorsomedial nucleus of the hypothalamus; ER, endoplasmic reticulum; F, fornix; FOXO, forkhead transcription factor; InsR, insulin receptors; IRS, insulin receptor substrate; Jak, Janus kinase; lepRb, leptin receptor; MSH, melanocyte-stimulating hormone; mTOR, mammalian target of rapamycin; nAChR, nicotinic acetylcholine receptor; Opt, optic tract; p85/p110, p85 and p110 subunit of phosphoinositol-3-kinase; PAM, peptidyl α-amidating monooxygenase; PC, prohormone convertase; POMC, pro-opiomelanocortin; PIP3, phosphatidylinositol3,4,5-triphosphate; PLCg1, phospholipase C gamma 1; POMC, pro-opiomelanocortin; PPARg, peroxisome-proliferator activated receptor gamma; PRCP, prolylcarboxypeptidase; PVH, paraventricular nucleus of the hypothalamus; ROS, reactive oxygen species; SON, supraoptic nucleus; STAT3, signal transducer and activator of transcription 3; TRPC, transient receptor potential canonical; UCP2, uncoupling protein 2; VMH, ventromedial nucleus of the hypothalamus.

Figure 3

Beneficial and detrimental factors regulating POMC neurons during prenatal and postnatal periods. POMC neurons maintain their physiological functions by autophagy and adult neurogenesis. However, inflammation, chronic ROS production, and ER stress that are induced by HFD feeding deteriorate POMC functions and projections. Prenatal factors, such as maternal nutritional states, have profound effects on POMC neuronal functions and thus on the whole-body energy and glucose homeostasis. Abbreviations: ER, endoplasmic reticulum; HF, high-fat; hNSC, hypothalamic neural stem cell; IKKβ, IκB kinase β; NF-κB, nuclear factor-κB; iPSC, inducible pluripotent stem cell; POMC, pro-opiomelanocortin; PPARg, peroxisome proliferator-activated receptor gamma; ROS, reactive oxygen species.