Hypothalamic SIRT1 prevents age-associated weight gain by improving leptin sensitivity in mice

• Published in: Diabetologia Vol. 57; no. 4; pp. 819 - 831
• Main Authors: Sasaki, Tsutomu, Kikuchi, Osamu, Shimpuku, Mayumi, Susanti, Vina Yanti, Yokota-Hashimoto, Hiromi, Taguchi, Ryo, Shibusawa, Nobuyuki, Sato, Takashi, Tang, Lijun, Amano, Kosuke, Kitazumi, Tomoya, Kuroko, Mitsutaka, Fujita, Yuki, Maruyama, Jun, Lee, Yong-soo, Kobayashi, Masaki, Nakagawa, Takashi, Minokoshi, Yasuhiko, Harada, Akihiro, Yamada, Masanobu, Kitamura, Tadahiro
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-04-2014; Springer; Springer Nature B.V
• Subjects: Age; Aging; Animals; Biological and medical sciences; Body fat; Calorimetry, Indirect; Cytokines; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Energy; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Genotype; Homeostasis; Human Physiology; Hypothalamus; Hypothalamus - drug effects; Hypothalamus - metabolism; Immunohistochemistry; Internal Medicine; Leptin - pharmacology; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice; Mice, Inbred C57BL; Obesity; Peripheral nervous system. Autonomic nervous system. Neuromuscular transmission. Ganglionic transmission. Electric organ; Phosphatase; Polymerase Chain Reaction; Proteins; Sirtuin 1 - genetics; Sirtuin 1 - metabolism; Stem cells; Vertebrates: nervous system and sense organs; Weight Gain - genetics; Weight Gain - physiology; Japan; NAD; POMC; Sympathetic activity; Diet-induced obesity; Food intake; Energy expenditure; Brown adipose tissue; AgRP; Hypothalamus; Leptin sensitivity; Endocrinopathy; Central nervous system; Prohormone; Weight gain; Encephalon; Autonomic nervous system; Proopiocortin; Age; Nutritional status; Obesity; Diabetes mellitus; Rodentia; Nutrition disorder; Adipokine; Sympathetic nervous system; Feeding; Vertebrata; Sensitivity; Mammalia; Diet; Mouse; Animal; Leptin
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-013-3140-5

Aims/hypothesis
Obesity is associated with ageing and increased energy intake, while restriction of energy intake improves health and longevity in multiple organisms; the NAD
+
-dependent deacetylase sirtuin 1 (SIRT1) is implicated in this process. Pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons in the arcuate nucleus (ARC) of the hypothalamus are critical for energy balance regulation, and the level of SIRT1 protein decreases with age in the ARC. In the current study we tested whether conditional
Sirt1
overexpression in mouse POMC or AgRP neurons prevents age-associated weight gain and diet-induced obesity.
Methods
We targeted
Sirt1
cDNA sequence into the
Rosa26
locus and generated conditional
Sirt1
knock-in mice. These mice were crossed with mice harbouring either
Pomc-Cre
or
Agrp-Cre
and the metabolic variables, food intake, energy expenditure and sympathetic activity in adipose tissue of the resultant mice were analysed. We also used a hypothalamic cell line to investigate the molecular mechanism by which
Sirt1
overexpression modulates leptin signalling.
Results
Conditional
Sirt1
overexpression in mouse POMC or AgRP neurons prevented age-associated weight gain; overexpression in POMC neurons stimulated energy expenditure via increased sympathetic activity in adipose tissue, whereas overexpression in AgRP neurons suppressed food intake. SIRT1 improved leptin sensitivity in hypothalamic neurons in vitro and in vivo by downregulating protein-tyrosine phosphatase 1B, T cell protein-tyrosine phosphatase and suppressor of cytokine signalling 3. However, these phenotypes were absent in mice consuming a high-fat, high-sucrose diet due to decreases in ARC SIRT1 protein and hypothalamic NAD
+
levels.
Conclusions/interpretation
ARC SIRT1 is a negative regulator of energy balance, and decline in ARC SIRT1 function contributes to disruption of energy homeostasis by ageing and diet-induced obesity.