ex-527 and Body-Weight

Food consumption is fundamental for life, and eating disorders often result in devastating or life-threatening conditions. Anorexia nervosa (AN) is characterized by a persistent restriction of energy intake, leading to lowered body weight, constant fear of gaining weight, and psychological disturbances of body perception. Herein, we demonstrate that SIRT1 inhibition, both genetically and pharmacologically, delays the onset and progression of AN behaviors in activity-based anorexia (ABA) models, while SIRT1 activation accelerates ABA phenotypes. Mechanistically, we suggest that SIRT1 promotes progression of ABA, in part through its interaction with NRF1, leading to suppression of a NMDA receptor subunit Grin2A. Our results suggest that AN may arise from pathological positive feedback loops: voluntary food restriction activates SIRT1, promoting anxiety, hyperactivity, and addiction to starvation, exacerbating the dieting and exercising, thus further activating SIRT1. We propose SIRT1 inhibition can break this cycle and provide a potential therapy for individuals suffering from AN.

Topics: Animals; Anorexia Nervosa; Body Weight; Carbazoles; Disease Models, Animal; Female; Gene Expression Regulation; Heterocyclic Compounds, 4 or More Rings; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nerve Tissue Proteins; Nuclear Respiratory Factor 1; Phenotype; Receptors, N-Methyl-D-Aspartate; Resveratrol; Sirtuin 1; Stress, Mechanical; Up-Regulation

The consumption of a high-fat diet (HFD) and obesity have been associated not only with metabolic diseases but also with neuropsychiatric diseases, such as depression and anxiety. However, results on the effects of an HFD on anxiety are controversial, since both anxiogenic and anxiolytic effects have been reported. In this study, we evaluated the effects of both short- and long-term intake of an HFD on anxiety-like behaviors. To explore the impact of time on the association between an HFD and anxiety, mice were fed with an HFD for 4 weeks or 12 weeks. Compared with control-diet mice, mice given an HFD for 4 weeks displayed anxiolytic-like behaviors. At the same time, we observed decreased SIRT1 expression in the mPFC and the amygdala of HFD-fed mice. Moreover, resveratrol, an activator of SIRT1, reversed the anxiolytic-like behaviors in HFD-fed mice. However, after 12 weeks of consuming a high-fat diet, mice did not exhibit any anti-anxiety behavior or further decreases in SIRT1 expression in the aforementioned brain regions compared with CD-fed mice. When EX-527, a SIRT1 inhibitor, was intraperitoneally injected, we observed anxiolytic effects in the CD-fed mice but not in the 12-week HFD-fed mice. Collectively, our data demonstrate that exposure to a short-term HFD can induce anxiolytic behaviors, which may be associated with decreased SIRT1 in the mPFC and the amygdala. However, this effect is abolished when the high-fat diet is extended to 12 weeks. Together, these results demonstrate that SIRT1 plays an essential role in regulating mood-related behaviors in HFD-fed mice.

Topics: Animals; Anxiety; Blood Glucose; Body Weight; Brain; Carbazoles; Diet, High-Fat; Gene Expression Regulation; Male; Mice, Inbred C57BL; Psychotropic Drugs; Resveratrol; Sirtuin 1; Stilbenes; Time Factors

In the periphery, the nutrient-sensing enzyme Sirtuin 1 (silent mating type information regulation 2 homolog 1 [Sirt1]) reduces body weight in diet-induced obese (DIO) rodents. However, the role of Sirt1 in the brain, particularly the hypothalamus, in body weight and energy balance regulation is debated. Among the first studies to reveal that central Sirt1 regulates body weight came from experiments in our laboratory using Sprague Dawley rats. In that study, central inhibition of Sirt1 decreased body weight and food intake as a result of a Forkhead box protein O1 (FoxO1)-mediated increase in the anorexigenic proopiomelanocortin (POMC) and decrease in the orexigenic Agouti-related peptide in the hypothalamic arcuate nucleus. Here, we demonstrate that central inhibition of Sirt1 in DIO decreased body weight and increased energy expenditure at higher levels as compared with the lean counterpart. Brain Sirt1 inhibition in DIO increased acetylated FoxO1, which, in turn, increased phosphorylated FoxO1 via improved insulin/pAKT signaling. Elevated acetylated FoxO1 and phosphorylated FoxO1 increased POMC along with the α-MSH maturation enzyme carboxypeptidase E, which resulted in more of the bioactive POMC product α-MSH released into the paraventricular nucleus. Increased in α-MSH led to augmented TRH levels and circulating T3 levels (thyroid hormone). These results indicate that inhibiting hypothalamic Sirt1 in DIO enhances the activity of the hypothalamic-pituitary-thyroid axis, which stimulates energy expenditure. Because we show that blocking central Sirt1 causes physiological changes that promote a negative energy balance in an obese individual, our results support brain Sirt1 as a significant target for weight loss therapeutics.

Topics: Acetylation; alpha-MSH; Animals; Arcuate Nucleus of Hypothalamus; Blotting, Western; Body Weight; Carbazoles; Carboxypeptidase H; Cell Line, Tumor; Diet, High-Fat; Eating; Energy Metabolism; Forkhead Transcription Factors; Male; Nerve Tissue Proteins; Obesity; Paraventricular Hypothalamic Nucleus; Pro-Opiomelanocortin; Rats; Rats, Sprague-Dawley; RNA Interference; Signal Transduction; Sirtuin 1