Endocrine Abstracts

The brain is critically involved in the regulation of energy balance and glucose homeostasis. Depending on the levels of energy available in our body, the activity of a group of hypothalamic neurons expressing the neuropeptidergic marker proopiomelanocortin (POMC) changes and it plays a key role in maintaining energy balance. When POMC neuronal activity is altered, this can lead to impaired energy homeostasis and therefore to obesity. However, POMC neurons are highly diverse, and whether or not such heterogeneity is implicated in the development of diet-induced obesity (DIO) remains unknown. Here, we used a lineage-tracing approach in combination with immunofluorescence, fluorescent in situ hybridization, and ex-vivo hypothalamic slice electrophysiology, to characterize the molecular and functional heterogeneity of POMC neurons in control lean and DIO mice. Thanks to the genetic strategy employed, we have successfully ’traced’ with a reporter protein POMC neurons in adult mice, thereby allowing to study these neuronal cells independently from the expression of their main marker POMC. Three subpopulations of POMC neurons could be identified: neurons expressing high levels of POMC (POMC-high), neurons with low POMC expression (POMC-low), and neurons with no POMC expression (POMC-’ghost’). Notably, chronic exposure to a high-fat diet (HFD) led to alterations in the peptidergic and molecular machinery of the POMC-high subpopulation, but did not affect POMC-low or POMC-ghost neurons. Thus, our data suggest that DIO leads to selective functional alterations in specific POMC neuronal clusters. The approach proposed may be used in the future to map the functional relationship between specific subpopulations of POMC neurons and obesity pathogenesis.