Leptin receptor neurons in the dorsomedial hypothalamus require distinct neuronal subsets for thermogenesis and weight loss

Authors: FRANCOIS, MARIE - Pennington Biomedical Research Center; KAISER, LAURA - Pennington Biomedical Research Center; HE, YANLIN - Pennington Biomedical Research Center; XU, YONG - Children'S Nutrition Research Center (CNRC); SALBAUM, J. MICHAEL - Pennington Biomedical Research Center; YU, SANGHO - Pennington Biomedical Research Center; MORRISON, CHRISTOPHER - Pennington Biomedical Research Center; BERTHOUD, HANS-RUDOLF - Pennington Biomedical Research Center; MUNZBERG, HEIKE - Pennington Biomedical Research Center

Submitted to: Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/7/2024
Publication Date: 12/12/2024
Citation: Francois, M., Kaiser, L., He, Y., Xu, Y., Salbaum, J., Yu, S., Morrison, C.D., Berthoud, H., Munzberg, H. 2024. Leptin receptor neurons in the dorsomedial hypothalamus require distinct neuronal subsets for thermogenesis and weight loss. Metabolism. 163. Article 156100. https://doi.org/10.1016/j.metabol.2024.156100.
DOI: https://doi.org/10.1016/j.metabol.2024.156100

Interpretive Summary: The dorsomedial hypothalamus (DMH) is a brain region that receives signals from the preoptic area (POA), where temperature affects how the body manages energy use and food intake. Neurons in the POA that are activated by warmth can lower energy expenditure by communicating with neurons in the DMH that project to brown adipose tissue (BAT). Previous research identified neurons in the DMH that have leptin receptors (Lepr) and influence metabolism. In this study, we explored whether these DMH neurons use the neurotransmitters glutamate or GABA. We found that the Lepr-expressing neurons in the DMH are made up of equal parts glutamatergic (using glutamate) and GABAergic (using GABA) neurons. Interestingly, when we activated these neurons, both types were able to increase energy expenditure and movement. However, they did not replicate the positive metabolic effects seen when activating the Lepr neurons. We also discovered that the BAT-projecting neurons in the DMH that connect to the raphe pallidus (RPa) are exclusively glutamatergic, while GABAergic neurons overlap with Lepr neurons in another area, indicating different pathways for regulating energy expenditure. Further experiments showed that many of the Lepr neurons in the DMH were inhibited by leptin, but blocking synaptic activity increased the number of neurons activated by leptin. This suggests that Lepr neurons might inhibit the DMH neurons. In conclusion, both GABAergic and glutamatergic neurons in the DMH play a role in metabolic regulation, and their stimulation may work together for positive metabolic effects. Our findings highlight the importance of DMH Lepr neurons in integrating signals related to temperature and energy balance in the body. This research enhances our understanding of thermoregulation and points to the DMH-Lepr neurons as key players in maintaining energy balance and body weight.

Technical Abstract: The dorsomedial hypothalamus (DMH) receives inputs from the preoptic area (POA), where ambient temperature mediates physiological adaptations of energy expenditure and food intake. Warm-activated POA neurons suppress energy expenditure via brown adipose tissue (BAT) projecting neurons in the dorsomedial hypothalamus/dorsal hypothalamic area (dDMH/DHA). Our earlier work identified leptin receptor (Lepr)-expressing, BAT-projecting dDMH/DHA neurons that mediate metabolic leptin effects. Yet, the neurotransmitter (glutamate or GABA) used by dDMH/DHALepr neurons remains unexplored and was investigated in this study using mice. We report that dDMH/DHALepr neurons represent equally glutamatergic and GABAergic neurons. Surprisingly, chemogenetic activation of glutamatergic and/or GABAergic dDMH/DHA neurons were capable to increase energy expenditure and locomotion, but neither reproduced the beneficial metabolic effects observed after chemogenetic activation of dDMH/DHALepr neurons. We clarify that BAT-projecting dDMH/DHA neurons that innervate the raphe pallidus (RPa) are exclusively glutamatergic Lepr neurons. In contrast, projections of GABAergic or dDMH/DHALepr neurons overlapped in the ventromedial arcuate nucleus (vmARC), suggesting distinct energy expenditure pathways. Brain slice patch clamp recordings further demonstrate a considerable proportion of leptin-inhibited dDMH/DHALepr neurons, while removal of pre-synaptic (indirect) effects with synaptic blocker increased the proportion of leptin-activated dDMH/DHALepr neurons, suggesting that pre-synaptic Lepr neurons inhibit dDMH/DHALepr neurons. We conclude that stimulation of BAT-related, GABA- and glutamatergic dDMH/DHALepr neurons in combination mediate the beneficial metabolic effects. Our data support the idea that dDMH/DHALepr neurons integrate upstream Lepr neurons (e.g., originating from POA and ARC). We speculate that these neurons manage dynamic adaptations to a variety of environmental changes including ambient temperature and energy state. SIGNIFICANCE STATEMENT: Our earlier work identified leptin receptor expressing neurons in the dDMH/DHA as an important thermoregulatory site. Dorsomedial hypothalamus (DMH) Lepr neurons participate in processing and integration of environmental exteroceptive signals like ambient temperature and circadian rhythm, as well as interoceptive signals including leptin and the gut hormone glucagon-like-peptide-1 (GLP1). The present work further characterizes dDMH/DHALepr neurons as a mixed glutamatergic and GABAergic population, but with distinct axonal projection sites. Surprisingly, select activation of glutamatergic and/or GABAergic populations are all able to increase energy expenditure, but are unable to replicate the beneficial metabolic effects observed by Lepr activation. These findings highlighting dDMH/DHA Lepr neurons as a distinct subgroup of glutamatergic and GABAergic neurons that are under indirect and direct influence of the interoceptive hormone leptin and if stimulated are uniquely capable to mediate beneficial metabolic effects. Our work significantly expands our knowledge of thermoregulatory circuits and puts a spotlight onto DMH-Lepr neurons for the integration into whole body energy and body weight homeostasis.