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Fasting‐ and ghrelin‐induced food intake is regulated by NAMPT in the hypothalamus
Author(s) -
Guia Roldan M.,
Hassing Anna S.,
Skov Louise J.,
Ratner Cecilia,
Plucińska Kaja,
Madsen Søren,
Diep Thi A.,
Dela Cruz Gelo V.,
Trammell Samuel A.J.,
Sustarsic Elahu G.,
Emanuelli Brice,
Gillum Matthew P.,
GerhartHines Zach,
Holst Birgitte,
Treebak Jonas T.
Publication year - 2020
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.13437
Subject(s) - ghrelin , medicine , endocrinology , nicotinamide phosphoribosyltransferase , hypothalamus , energy homeostasis , leptin , diet induced obese , arcuate nucleus , appetite , biology , nad+ kinase , obesity , insulin resistance , hormone , enzyme , biochemistry
Aim Neurons in the arcuate nucleus of the hypothalamus are involved in regulation of food intake and energy expenditure, and dysregulation of signalling in these neurons promotes development of obesity. The role of the rate‐limiting enzyme in the NAD + salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), for regulation energy homeostasis by the hypothalamus has not been extensively studied. Methods We determined whether Nampt mRNA or protein levels in the hypothalamus of mice were affected by diet‐induced obesity, by fasting and re‐feeding, and by leptin and ghrelin treatment. Primary hypothalamic neurons were treated with FK866, a selective inhibitor of NAMPT, or rAAV carrying shRNA directed against Nampt , and levels of reactive oxygen species (ROS) and mitochondrial respiration were assessed. Fasting and ghrelin‐induced food intake was measured in mice in metabolic cages after intracerebroventricular (ICV)‐mediated FK866 administration. Results NAMPT levels in the hypothalamus were elevated by administration of ghrelin and leptin. In diet‐induced obese mice, both protein and mRNA levels of NAMPT decreased in the hypothalamus. NAMPT inhibition in primary hypothalamic neurons significantly reduced levels of NAD + , increased levels of ROS, and affected the expression of Agrp , Pomc and genes related to mitochondrial function. Finally, ICV‐induced NAMPT inhibition by FK866 did not cause malaise or anhedonia, but completely ablated fasting‐ and ghrelin‐induced increases in food intake. Conclusion Our findings indicate that regulation of NAMPT levels in hypothalamic neurons is important for the control of fasting‐ and ghrelin‐induced food intake.