Agrp Neurons Mediate Sirt1's Action on the Melanocortin System and Energy Balance: Roles for Sirt1 in Neuronal Firing and Synaptic Plasticity

Abstract

Sirt1 has been associated with various effects of calorie restriction, including an increase in lifespan. Here we show in mice that a central regulatory component in energy metabolism, the hypothalamic melanocortin system, is affected by Sirt1, which promotes the activity and connectivity of this system resulting in negative energy balance. In adult mice, the pharmacological inhibition of brain Sirt1 activity decreased Agrp neuronal activity and the inhibitory tone on the anorexigenic POMC neurons, as measured by the number of synaptic inputs to these neurons. When a Sirt1 inhibitor (EX-527) was injected either peripherally (i.p., 10 mg/kg) or directly into the brain (i.c.v., 1.5 nmol/mouse), it decreased both food intake during the dark cycle and ghrelin-induced food intake. This effect on feeding is mediated by upstream melanocortin receptors, because the MC4R antagonist, SHU9119, reversed Sirt1's effect on food intake. This action of Sirt1 required an appropriate shift in the mitochondrial redox state: in the absence of such an adaptation enabled by the mitochondrial protein, UCP2, Sirt1-induced cellular and behavioral responses were impaired. In accordance with the pharmacological results, the selective knock-out of Sirt1 in hypothalamic Agrp neurons through the use of Cre-Lox technology decreased electric responses of Agrp neurons to ghrelin and decreased food intake, leading to decreased lean mass, fat mass, and body weight. The present data indicate that Sirt1 has a central mode of action by acting on the NPY/Agrp neurons to affect body metabolism.

Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses

“…Our data support the notion that the CNS can affect immune functions (40,41), which can supersede the predicted effects of circulating metabolic hormones, such as leptin. These results, together with our recent demonstration of specific behavioral and metabolic phenotypes of AgRP-Sirt1 KO animals (3,4), suggest that traits of altered motivated behaviors and basic metabolic parameters can be predictors of adaptive immune system phenotypes.…”

“…We used the knockdown model of Sirt1 in the NPY/AgRP neurons previously described (4). Briefly, we used Cre/Lox technology to knock down the catalytic domain of Sirt1 in this population of cells.…”

“…As mentioned above, selective knockdown of Sirt1 in hypothalamic AgRP neurons alters the central perception of hunger, inducing a series of metabolic/behavioral adaptations that resemble those of a satiety phenotype despite reduced food intake and body fat mass (4). Thus, in this study we aimed to determine whether selective ablation of Sirt1 expression in AgRP neurons affects peripheral adaptive immunity by analyzing lymphoid organs' immune phenotype, thymic selection, in vitro/in vivo regulatory/proinflammatory immune responses, and autoimmune disease susceptibility in mice.…”

“…immune system | sirtuins H ypothalamic Agouti-related peptide-expressing (AgRP) neurons are mandatory for feeding and survival (1, 2) and they mediate effects of the hystone deacetylase Sirtuin 1 (Sirt1) on energy metabolism (3,4). Behavioral and metabolic adaptations to low energy availability are enabled by AgRP neurons, but it is unknown whether these neurons are involved in the regulation of other tissue functions key to survival, such as adaptive immune responses.…”

Do Sirtuins Promote Mammalian Longevity?: A Critical Review on Its Relevance to the Longevity Effect Induced by Calorie Restriction

“…SIRT1 is expressed in the orexigenic neuropeptide Y (NPY)/Agouti-related peptide (AGRP) and anorexigenic proopiomelanocortin (POMC) neurons, which are major components in regulating feeding and energy expenditure in the arcuate nucleus of the hypothalamus (Sasaki and Kitamura, 2010). Several studies in mice and rats reported that SIRT1 regulates food intake and body weight by acting on the NPY/AGRP and POMC neurons (Cakir et al, 2009;Dietrich et al, 2010). …”