POMC neuronal heterogeneity in energy balance and beyond: an integrated view

Abstract

Hypothalamic AgRP and POMC neurons are conventionally viewed as the yin and yang of the body's energy status, since they act in an opposite manner to modulate appetite and systemic energy metabolism. However, although AgRP neurons' functions are comparatively well understood, a unifying theory of how POMC neuronal cells operate has remained elusive, probably due to their high level of heterogeneity, which suggests that their physiological roles might be more complex than initially thought. In this Perspective, we propose a conceptual framework that integrates POMC neuronal heterogeneity with appetite regulation, whole-body metabolic physiology and the development of obesity. We highlight emerging evidence indicating that POMC neurons respond to distinct combinations of interoceptive signals and food-related cues to fine-tune divergent metabolic pathways and behaviours necessary for survival. The new framework we propose reflects the high degree of developmental plasticity of this neuronal population and may enable progress towards understanding of both the aetiology and treatment of metabolic disorders.

Fig. 1 |. Current classification methods used to identify POMC neuron subtypes.

Schematic of the unbiased (scRNA-seq analysis) and biased methods (neuronal tracing, electrophysiology, cell labelling (fluorescence in situ hybridization (FISH), immunohistochemistry (IHC) and RNAScope for molecular marker, neurotransmitter and neuropeptide expression) and mouse genetics) used to date for identifying and characterizing POMC neurons. Note that the expression of receptors, neuropeptides and neurotransmitters at the level of the cells is only representative. The question marks represent receptors or other molecular markers that are still to be discovered. 3rd V: third ventricle; Glut, glutamate. Figure adapted with permission from C. Padgett.

Fig. 2 |. Mode(s) of action of different subsets of POMC neurons for the regulation of energy balance.

a, Different subsets of hypothalamic POMC neurons can modulate different outputs. b, Different subsets of POMC neurons can also converge to modulate the same output and/or the same subsets of cells can act on multiple outputs. Figure adapted with permission from C. Padgett.

Fig. 3 |. Physiological roles of POMC neurons beyond energy balance.

Beyond a critical role in energy balance, POMC neurons orchestrate behavioural and physiological responses necessary for survival, including modulation of pain, stress/anxiety, fear, locomotion and cardiovascular responses. Figure adapted with permission from C. Padgett.