SIRT1 Promotes the Central Adaptive Response to Diet Restriction through Activation of the Dorsomedial and Lateral Nuclei of the Hypothalamus

Abstract

Diet restriction retards aging and extends lifespan by triggering adaptive mechanisms that alter behavioral, physiological, and biochemical responses in mammals. Little is known about the molecular pathways evoking the corresponding central response. One factor that mediates the effects of diet restriction is the mammalian nicotinamide adenine dinucleotide (NAD)-dependent deacetylase SIRT1. Here we demonstrate that diet restriction significantly increases SIRT1 protein levels and induces neural activation in the dorsomedial and lateral hypothalamic nuclei. Increasing SIRT1 in the brain of transgenic (BRASTO) mice enhances neural activity specifically in these hypothalamic nuclei, maintains a higher range of body temperature, and promotes physical activity in response to different dietrestricting paradigms. These responses are all abrogated in Sirt1-deficient mice. SIRT1 upregulates expression of the orexin type 2 receptor specifically in these hypothalamic nuclei in response to diet-restricting conditions, augmenting response to ghrelin, a gut hormone whose levels increase in these conditions. Our results suggest that in the hypothalamus, SIRT1 functions as a key mediator of the central response to low nutritional availability, providing insight into the role of the hypothalamus in the regulation of metabolism and aging in mammals.

Hypothalamic Sirt1 protects terminal Schwann cells and neuromuscular junctions from age‐related morphological changes

“…S100‐GFP mice (generous gift from Dr. Susan Mackinnon, Washington University School of Medicine, St. Louis, MO) utilize the S100B promoter to drive GFP expression in all glial cells (Feng et al., 2000). We also used two types of Sirt1 mice: transgenic mice (7‐, 16‐, 20‐, 25‐ and 33‐month‐old) where brain‐specific Sirt1 was overexpressed (BRASTO mice (Satoh et al., 2010, 2013) and shRNA‐ Sirt1 ‐injected mice (3‐month‐old) where Sirt1 was knocked down in the DMH using lentivirus and the stereotactic injection procedure described previously (Satoh et al., 2013)). The BRASTO mice with an HA‐tagged Sirt1 transgene driven by the mouse prion promoter were backcrossed to C57BL/6J for 8 to 10 generations (Satoh et al., 2010).…”

“…We also used two types of Sirt1 mice: transgenic mice (7‐, 16‐, 20‐, 25‐ and 33‐month‐old) where brain‐specific Sirt1 was overexpressed (BRASTO mice (Satoh et al., 2010, 2013) and shRNA‐ Sirt1 ‐injected mice (3‐month‐old) where Sirt1 was knocked down in the DMH using lentivirus and the stereotactic injection procedure described previously (Satoh et al., 2013)). The BRASTO mice with an HA‐tagged Sirt1 transgene driven by the mouse prion promoter were backcrossed to C57BL/6J for 8 to 10 generations (Satoh et al., 2010). Mice in the aging cohorts were carefully inspected every day for all experiments, and both sexes were used for experiments.…”

“…Recent studies have demonstrated that hypothalamic Sirt1 regulates mammalian aging and longevity in mice. Stereotactic injection of Sirt1 ‐expressing lentiviruses into the dorsomedial hypothalamus (DMH) of aged adult wild‐type (WT) mice ameliorates age‐associated declines in physical activity and body temperature, supporting the notion that the hypothalamus, specifically the DMH, is one of the control centers for mammalian aging and longevity (Satoh et al., 2010, 2013). Mice with brain‐specific overexpression of Sirt1 (BRASTO) show a significant delay in aging with extended lifespans in both males and females (Satoh et al., 2013).…”

Calorie restriction and sirtuins revisited

“…In addition, SIRT1 in the ventromedial hypothalamic (VMH) neurons determines physiological outputs to ghrelin signaling (Velasquez et al 2011;Porteiro et al 2013). SIRT1 in the dorsomedial hypothalamus (DMH) and lateral hypothalamus (LH) is induced by CR and mediates outputs such as physical activity and body temperature by determining the levels of the orexin receptor 2 (Satoh et al 2010). Correspondingly, SIRT1 in the pro-opiomelanocortin (POMC) neurons (Ramadori et al 2010) protects against metabolic decline induced by high-fat diets.…”

Sirtuin-Dependent Metabolic Control and Its Role in the Aging Process

“…Moreover, loss-of-function and gain-of-function mouse studies have provided genetic evidences that indicate that SIRT1 is a key factor in the physiological response to CR (Imai, 2009). It is also important to highlight that SIRT1 has been related to the central response to low nutritional availability at the hypothalamus level probably playing an important role in the regulation of the whole metabolism in mammals (Satoh et al, 2010). Further, SIRT6 levels are also modulated by nutrient availability in a p53-independent mechanism.…”