Sirt1 rescues the obesity induced by insulin-resistant constitutively-nuclear FoxO1 in POMC neurons of male mice.

OBJECTIVE: The hypothalamus is the brain center that controls the energy balance. Anorexigenic proopiomelanocortin (POMC) neurons and orexigenic AgRP neurons in the arcuate nucleus of the hypothalamus plays critical roles in energy balance regulation. FoxO1 is a transcription factor regulated by insulin signaling that is deacetylated by Sirt1, a nicotinamide adenine dinucleotide- (NAD(+) -) dependent deacetylase. Overexpression of insulin-resistant constitutively-nuclear FoxO1 (CN-FoxO1) in POMC neurons leads to obesity, whereas Sirt1 overexpression in POMC neurons leads to leanness. Whether overexpression of Sirt1 in POMC neurons could rescue the obesity caused by insulin-resistant CN-FoxO1 was tested here. METHODS: POMC neuron-specific CN-FoxO1/Sirt1 double-KI (DKI) mice were analyzed. RESULTS: The obese phenotype of CN-FoxO1 KI mice was rescued in male DKI mice. Reduced O2 consumption, increased adiposity, and fewer POMC neurons observed in CN-FoxO1 mice were rescued in male DKI mice without affecting food intake and locomotor activity. Sirt1 overexpression decreased FoxO1 acetylation and protein levels without affecting its nuclear localization in mouse embryonic fibroblasts and hypothalamic N41 cells. CONCLUSIONS: Sirt1 rescues the obesity induced by insulin-resistant CN-FoxO1 in POMC neurons of male mice by decreasing FoxO1 protein through deacetylation. Sirt1 ameliorates obesity caused by a genetic model of central insulin resistance.

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

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.

Miglitol prevents diet-induced obesity by stimulating brown adipose tissue and energy expenditure independent of preventing the digestion of carbohydrates.

Miglitol is an alpha-glucosidase inhibitor that improves post-prandial hyperglycemia, and it is the only drug in its class that enters the bloodstream. Anecdotally, miglitol lowers patient body weight more effectively than other alpha-glucosidase inhibitors, but the precise mechanism has not been addressed. Therefore, we analyzed the anti-obesity effects of miglitol in mice and in the HB2 brown adipocyte cell line. Miglitol prevented diet-induced obesity by stimulating energy expenditure without affecting food intake in mice. Long-term miglitol treatment dose-dependently prevented diet-induced obesity and induced mitochondrial gene expression in brown adipose tissue. The anti-obesity effect was independent of preventing carbohydrate digestion in the gastrointestinal tract. Miglitol effectively stimulated energy expenditure in mice fed a high-fat high-monocarbohydrate diet, and intraperitoneal injection of miglitol was sufficient to stimulate energy expenditure in mice. Acarbose, which is a non-absorbable alpha glucosidase inhibitor, also prevented diet-induced obesity, but through a different mechanism: it did not stimulate energy expenditure, but caused indigestion, leading to less energy absorption. Miglitol promoted adrenergic signaling in brown adipocytes in vitro. These data indicate that circulating miglitol stimulates brown adipose tissue and increases energy expenditure, thereby preventing diet-induced obesity. Further optimizing miglitol's effect on brown adipose tissue could lead to a novel anti-obesity drug.

Necdin controls Foxo1 acetylation in hypothalamic arcuate neurons to modulate the thyroid axis.

The forkhead transcription factor Foxo1 regulates energy homeostasis by modulating gene expression in the hypothalamus. Foxo1 undergoes post-translational modifications such as phosphorylation and acetylation, which modulate its functional activities. Sirtuin1 (Sirt1), a nicotinamide adenine dinucleotide-dependent protein deacetylase, regulates the acetylation status of Foxo1 in mammalian cells. Necdin, a pleiotropic protein required for neuronal development and survival, interacts with both Sirt1 and p53 to facilitate p53 deacetylation. The necdin gene (Ndn), an imprinted gene transcribed only from the paternal allele, is strongly expressed in hypothalamic neurons. Here, we demonstrate that necdin controls the acetylation status of Foxo1 in vivo in hypothalamic arcuate neurons to modulate the thyroid function. Necdin forms a stable ternary complex with Sirt1 and Foxo1, diminishes Foxo1 acetylation, and suppresses the transcriptional activity of Foxo1 in vitro. Paternal Ndn mutant mice express high levels of acetylated Foxo1 and mRNAs encoding agouti-related protein and neuropeptide Y in the hypothalamus in vivo during the juvenile period. The mutant mice exhibit endocrine dysfunction characteristic of hypothalamic hypothyroidism. Chemically induced hyperthyroidism and hypothyroidism lead to hypothalamic responses similar to those under necdin-deficient and excessive conditions, respectively, suggesting that thyroid hormone serves as a negative regulator of this system. These results suggest that necdin regulates Foxo1 acetylation and neuropeptide gene expression in the arcuate neurons to modulate the hypothalamic-pituitary-thyroid axis during development.