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Maternal nutrition exerts profound and lasting effects on infant development, with implications extending beyond somatic growth to long-term brain function and metabolic health. For example, newborns from mothers with obesity or diabetes exhibit increased susceptibility to metabolic disorders, including insulin resistance (IR) and type 2 diabetes (T2D), often emerging in childhood or adolescence. While genetic inheritance contributes to this intergenerational risk, early-life nutritional exposures are increasingly recognized as primary drivers of persistent metabolic programming. Among key classes of nutrients, branched-chain amino acids (BCAAs)—leucine, isoleucine, and valine—have emerged as potent modulators of metabolic health in human adults. Elevated circulating BCAAs are among the most accurate predictors of future insulin resistance (IR) and T2D, with a two-fold increase in serum levels conferring a 2.5-fold risk of diabetes onset within 6–10 years. This elevation can directly cause organ toxicity, exacerbating metabolic deficits in a feed-forward loop. However, the extent to which maternal BCAA overnutrition during gestation and lactation impacts offspring metabolic programming and predisposes to dysfunction remains unclear.

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Dorsal raphe nucleus MC4R-GABAergic neurons regulate feeding and anxiety

Satoshi Yamagata, Francesca Copperi, Gavin Thomas White, Jung Dae Kim, Sabrina Diano

Dorsal raphe nucleus MC4R-GABAergic neurons regulate feeding and anxiety

Objective

The melanocortin receptor 4 (MC4R) plays a key role in the CNS regulation of metabolism. In addition to its role within the hypothalamus, other brain areas, including the dorsal raphe nucleus (DRN), express MC4R. However, the identity and role of these neurons in metabolism regulation are not fully understood. We performed studies to address these questions.

Methods

We generated Mc4r-cre;Vgat-FlpO and Mc4r-cre;Vglut2-FlpO mice to determine the contribution of these MC4R neuronal populations in DRN. We then chemogenetically activated or inhibited the GABAergic and glutamatergic populations of MC4R. Finally, we selectively deleted MC4R from these two neuronal populations and studied the impact on whole-body metabolism.

Results

We found that about 60% of DRN MC4R neurons are GABAergic (Vgat), while only about 20% are glutamatergic (Vglut2). Most of the projections onto DRN neurons originated from the arcuate nucleus (ARC)-POMC neurons, and only a small input from the nucleus of the solitary tract (NTS)-POMC neurons was identified. Significant projections of DRN MC4R/Vgat neurons were observed in the paraventricular nucleus of the hypothalamus (PVN). Chemogenetic activation or inhibition of MC4R/Vgat neurons increased or inhibited food intake, respectively. No effects were observed when the same approach was used in MC4R/Vglut2 neurons. Furthermore, only chemogenetic manipulation of the MC4R/Vgat neurons affected anxiety-like behavior, which was associated with changes in serotonin staining in the DRN. Finally, MC4R-selective deletion in Vgat but not Vglut2 neurons affected whole-body metabolism.

Conclusions

These findings suggest that DRN MC4R/Vgat neurons receiving projections from the ARC POMC neurons and projecting to the hypothalamic PVN play a role in metabolism regulation. In addition, this same DRN neuronal subpopulation affects anxiety-like behavior by modulating DRN serotonin neurons.

Articles in Press

Dorsal raphe nucleus MC4R-GABAergic neurons regulate feeding and anxiety

Satoshi Yamagata, Francesca Copperi, Gavin Thomas White, Jung Dae Kim, Sabrina Diano

Dorsal raphe nucleus MC4R-GABAergic neurons regulate feeding and anxiety

Objective

The melanocortin receptor 4 (MC4R) plays a key role in the CNS regulation of metabolism. In addition to its role within the hypothalamus, other brain areas, including the dorsal raphe nucleus (DRN), express MC4R. However, the identity and role of these neurons in metabolism regulation are not fully understood. We performed studies to address these questions.

Methods

We generated Mc4r-cre;Vgat-FlpO and Mc4r-cre;Vglut2-FlpO mice to determine the contribution of these MC4R neuronal populations in DRN. We then chemogenetically activated or inhibited the GABAergic and glutamatergic populations of MC4R. Finally, we selectively deleted MC4R from these two neuronal populations and studied the impact on whole-body metabolism.

Results

We found that about 60% of DRN MC4R neurons are GABAergic (Vgat), while only about 20% are glutamatergic (Vglut2). Most of the projections onto DRN neurons originated from the arcuate nucleus (ARC)-POMC neurons, and only a small input from the nucleus of the solitary tract (NTS)-POMC neurons was identified. Significant projections of DRN MC4R/Vgat neurons were observed in the paraventricular nucleus of the hypothalamus (PVN). Chemogenetic activation or inhibition of MC4R/Vgat neurons increased or inhibited food intake, respectively. No effects were observed when the same approach was used in MC4R/Vglut2 neurons. Furthermore, only chemogenetic manipulation of the MC4R/Vgat neurons affected anxiety-like behavior, which was associated with changes in serotonin staining in the DRN. Finally, MC4R-selective deletion in Vgat but not Vglut2 neurons affected whole-body metabolism.

Conclusions

These findings suggest that DRN MC4R/Vgat neurons receiving projections from the ARC POMC neurons and projecting to the hypothalamic PVN play a role in metabolism regulation. In addition, this same DRN neuronal subpopulation affects anxiety-like behavior by modulating DRN serotonin neurons.

SAVE THE DATE!

13th
Helmholtz Diabetes Conference 
Munich, 21-23. Sep 2026                                                                                                                             

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You are what you eat

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