Hypothalamic astrocyte NAD+ salvage pathway mediates the coupling of dietary fat overconsumption in a mouse model of obesity

Jae Woo Park, Se Eun Park, Wuhyun Koh, Won Hee Jang, Jong Han Choi, Eun Roh, Gil Myoung Kang, Seong Jun Kim, Hyo Sun Lim, Chae Beom Park, So Yeon Jeong, Sang Yun Moon, Chan Hee Lee, Sang Yeob Kim, Hyung Jin Choi, Se Hee Min, C. Justin Lee and Min-Seon Kim ()
Additional contact information
Jae Woo Park: University of Ulsan College of Medicine
Se Eun Park: University of Ulsan College of Medicine
Wuhyun Koh: Center for Cognition and Sociality, Life Science Cluster, Institute for Basic Science
Won Hee Jang: University of Ulsan College of Medicine
Jong Han Choi: Konkuk University Medical Center
Eun Roh: Hallym University Sacred Heart Hospital
Gil Myoung Kang: Asan Institute for Life Science
Seong Jun Kim: University of Ulsan College of Medicine
Hyo Sun Lim: University of Ulsan College of Medicine
Chae Beom Park: University of Ulsan College of Medicine
So Yeon Jeong: University of Ulsan College of Medicine
Sang Yun Moon: University of Ulsan College of Medicine
Chan Hee Lee: Hallym University
Sang Yeob Kim: Asan Medical Center
Hyung Jin Choi: Seoul National University College of Medicine
Se Hee Min: Asan Institute for Life Science
C. Justin Lee: Center for Cognition and Sociality, Life Science Cluster, Institute for Basic Science
Min-Seon Kim: Asan Institute for Life Science

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Nicotinamide adenine dinucleotide (NAD)+ serves as a crucial coenzyme in numerous essential biological reactions, and its cellular availability relies on the activity of the nicotinamide phosphoribosyltransferase (NAMPT)-catalyzed salvage pathway. Here we show that treatment with saturated fatty acids activates the NAD+ salvage pathway in hypothalamic astrocytes. Furthermore, inhibition of this pathway mitigates hypothalamic inflammation and attenuates the development of obesity in male mice fed a high-fat diet (HFD). Mechanistically, CD38 functions downstream of the NAD+ salvage pathway in hypothalamic astrocytes burdened with excess fat. The activation of the astrocytic NAMPT–NAD+–CD38 axis in response to fat overload induces proinflammatory responses in the hypothalamus. It also leads to aberrantly activated basal Ca2+ signals and compromised Ca2+ responses to metabolic hormones such as insulin, leptin, and glucagon-like peptide 1, ultimately resulting in dysfunctional hypothalamic astrocytes. Our findings highlight the significant contribution of the hypothalamic astrocytic NAD+ salvage pathway, along with its downstream CD38, to HFD-induced obesity.

Date: 2024
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DOI: 10.1038/s41467-024-46009-0

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