Synthesis of nicotinamide adenine dinucleotide (NAD+) decreases during aging, which is thought to limit the activity of enzymes that require it for their catalytic activity. Studies in animals indicate that replenishment of cellular NAD+ can have beneficial effects on aging and age-related diseases, but the situation in humans is less clear. Yoshino et al. report the effects of supplementation with the NAD+ precursor nicotinamide mononucleotide in overweight or obese postmenopausal women with prediabetes (see the Perspective by Hepler and Bass). The treatment improved insulin sensitivity in muscle, although a change in NAD+ content was not detected. The treatment also increased the expression of platelet-derived growth factor b. The results support potential therapeutic action of NAD+ supplementation in humans, but how various NAD+ precursors are processed in specific tissues remains to be fully explored.
Science , abe9985, this issue p. [1224][1]; see also abj0764, p. [1147][2]
In r
2The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA.
3Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
4Center for Theoretical Biological Physics, Rice University, Houston, TX 77005, USA.
5Division of Cell Biology, Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
6Division of Gene Regulation, Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
7Department of Physics, Institute of Biosciences, Letters and Exact Sciences, São Paulo State University (UNESP), São José do Rio Preto – SP, 15054-000, Brazil.
8BioImaging Facility, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
9Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech, Pudong 201210, China.
DiAntonio, Milbrandt honored for innovation, entrepreneurship
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Jean Allman and Lilianna Solnica-Krezel will receive Washington University in St. Louis’ 2021 faculty achievement awards, Chancellor Andrew D. Martin announced.
Allman, PhD, the J.H. Hexter Professor in the Humanities and professor of African and African American studies, as well as director of the Center for the Humanities, all in Arts & Sciences, will receive the Arthur Holly Compton Faculty Achievement Award. Solnica-Krezel, PhD, the Alan A. and Edith L. Wolff Distinguished Professor and head of the Department of Developmental Biology at the School of Medicine, will receive the Carl and Gerty Cori Faculty Achievement Award.
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Abstract
Obesity is a global epidemic causing morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-EM structure of the human MC4R-G
s signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. In addition, our findings indicate that Ca
2+ is required for agonist but not antagonist efficacy. These results fill a gap in understanding MC4R activation and could guide the design of future weight management drugs.View Full Text