Venue: Centre Broca
Defense in english
Team: Energy balance and obesity
Thesis supervisor: Carmelo Quarta
Single-cell mapping of POMC neurons in obesity
The hypothalamus contains heterogeneous neurons with different functional identities, a critical feature for brain-mediated control of body weight and energy metabolism. Alterations in the synaptic activity and neuropeptide production capacity of neurons in this brain region are implicated in the pathogenesis of obesity and its associated metabolic sequelae. However, the specific neuronal subtypes that contribute to metabolic control or brain-mediated disease progression remain to be elucidated. Hypothalamic pro-opiomelanocortin (POMC) neurons, which are responsible for the induction of satiety, represent a potential therapeutic target. Although traditionally thought to be relatively homogeneous, recent studies have revealed multiple layers of heterogeneity within hypothalamic POMC-expressing neurons. In adult mammals, mature POMC neurons express variable levels of their main marker Pomc. However, no study has thus far investigated the relationship between the molecular and functional heterogeneity of subsets of POMC neurons expressing different levels of their main identity marker. Diet-induced obesity (DIO) is associated with functional alterations involving POMC neurons, but most of the studies have so far explored how dietary or metabolic cues affect the whole neuronal population, without providing detailed information on possible cell-specific effects.
This project aimed to (i) investigate the molecular and functional heterogeneity of POMC neurons at single cell level under physiological conditions and (ii) uncover the cell-specific impact of DIO on POMC neuron function. By combining genetic mouse models for lineage tracing of mature POMC neurons with multimodal single-cell profiling approaches, we revealed a subpopulation of ‘Ghost’ neurons endowed with postnatal identity plasticity. Compared to ‘classical’ POMC neurons, Ghost neurons exhibit negligible expression of Pomc and other cell identity markers, impaired functional responses to nutrient and hormonal cues, and distinct neuroanatomical properties. Intriguingly, the number of Ghost neurons is increased in DIO mice, independent of neurogenesis or cell death, and this identity switch can be rescued by diet-induced weight loss. DIO did not lead to global changes but rather to cell-specific adaptations in the electrophysiological properties in one clusters of cells that resemble the identified Ghost neurons.
My data, therefore, shed new light on the high degree of molecular and functional heterogeneity of POMC neurons under both physiological conditions and obesogenic states. Such heterogeneity includes the presence of atypical clusters of POMC cells with atypical molecular and functional identity that are insensitive to acute dietary cues. Moreover, my data suggests that specialised hypothalamic neurons can lose or possibly regain their functional identity throughout adult life in response to changes in body weight, challenging the current dogma that neuronal fate is ‘fixed’ after development. Thus, prolonged exposure to dietary cues in adulthood may alter mechanisms of neuronal identity maintenance, and this novel mechanism may potentially contribute to the progression of diet-induced obesity and its associated health sequelae.
Key words: POMC neurons, Heterogeneity, Hypothalamus, Obesity
Quarta Carmelo, Dr
Gangarossa Guiseppe, Pr
Magnan Christophe, Pr
Rovere Carole, Dr
Moisan Marie-Pierre, Dr
1. Leon S, Nadjar A, Quarta C. Microglia–Neuron Crosstalk in Obesity: Melodious Interaction or Kiss of Death? (2021) International Journal of Molecular Sciences. 2021.22(10):5243.
2. Saucisse N, Mazier W, Simon V, Binder E, Catania C, Bellocchio L, Romanov RA, Leon S, Matias I, Zizzari P, Quarta C, Cannich A, Meece K, Gonzales D, Clark S, Becker JM, Yeo GSH, Merkle FT, Wardlaw SL, Harkany T, Massa F, Marsicano G, Cota D (2020). POMC neurons functional heterogeneity relies on mTORC1 signaling. Cell Rep. 2021 Oct 12;37(2):109800. doi: 10.1016/j.celrep.2021.109800.
3. Leyrolle Q, Decoeur F, Dejean C, Bosch-Bouju C, Morel L, Leon S, Amadieu C, Sere A, Schwendimann L, Aubert A, De Smedt-Peyrusse V, Grégoire S, Bretillon L, Acar N, Pallet V, Joffre C, Tremblay ME, Gressens P, Layé S, Nadjar A (2021). Dietary n-3 PUFA deficiency disrupts myelination processes during brain development, Glia. 2022 Jan;70(1):50-70. doi: 10.1002/glia.24088. Epub 2021 Sep 14.