Regulation of energy homeostasis by hypothalamic Sirtuin 1 and endoplasmic reticulum stress

Central regulation of energy balance involves a coordination of several hormonal and nutritional inputs to the hypothalamus by enzymes with activities coupled to nutrient or energy levels. Sirt1 (Sirtuin 1) is an NAD+ (nicotinamide adenine dinucleotide) dependent deacetylase with some of its substrates being involved in the signaling pathways of hypothalamic energy balance. However, the biological significance of hypothalamic Sirt1 in the regulation of food intake and body weight is unknown.;This work demonstrates that inhibition of hypothalamic Sirt1 activity or expression in the rat results in decreased food intake and body weight gain. This regulation depends on the deacetylation and activation of Forkhead transcription factor FoxO1 by Sirt1, and inhibition of S6K1 (ribosomal S6 kinase) signaling. Sirt1 regulates food intake through melanocortin signaling, which involves the negative regulation of POMC (pro-opiomelanocortin) and positive regulation of Agrp (Agouti related peptide) expression by Sirt1. Upon development of diet-induced obesity (DIO), hypothalamic Sirt1 expression increases but POMC mRNA expression remains unaltered. However, POMC post-translational processing is downregulated in DIO rats. DIO rats exhibit elevated hypothalamic endoplasmic reticulum (ER) stress in the arcuate nucleus. ER stress results in increased expression of negative regulators of leptin signaling: Suppressor of cytokine signaling 3 (SOCS3) and protein tyrosine phosphatase 1B (PTP1B). In addition, ER stress attenuates POMC post-translational expression through translational suppression and down-regulation of prohormone convertase 2. This in turn results in decreased production of the POMC derived anorectic peptide alphaMSH. alphaMSH is a potent inducer of Thyrotropin Releasing Hormone (TRH) expression. Despite decreased alphaMSH levels, the thyroid axis in obese rats is elevated. The paraventricular nucleus (PVN) of the hypothalamus, where hypophysiotropic TRH neurons are located does not develop ER stress and remains leptin sensitive. Increased leptin input to TRH neurons results in elevated thyroid axis in DIO rats.;This work provides a mechanistic understanding of how an enzyme (Sirt1) involved in organismal longevity regulates energy metabolism at the central level. Taken together with the role of ER stress in obesity, manipulations targeting Sirt1 activity and ER homeostasis could result in promising therapies for metabolic diseases.