title: SIRT1 enhances glucose tolerance by potentiating brown adipose tissue function.
abstract: OBJECTIVE
  SIRT1 has been proposed to be a key signaling node linking changes in energy metabolism to transcriptional adaptations. Although SIRT1 overexpression is protective against diverse metabolic complications, especially in response to high-fat diets, studies aiming to understand the etiology of such benefits are scarce. Here, we aimed to identify the key tissues and mechanisms implicated in the beneficial effects of SIRT1 on glucose homeostasis.
  
  
  METHODS
  We have used a mouse model of moderate SIRT1 overexpression, under the control of its natural promoter, to evaluate glucose homeostasis and thoroughly characterize how different tissues could influence insulin sensitivity.
  
  
  RESULTS
  Mice with moderate overexpression of SIRT1 exhibit better glucose tolerance and insulin sensitivity even on a low fat diet. Euglycemic-hyperinsulinemic clamps and in-depth tissue analyses revealed that enhanced insulin sensitivity was achieved through a higher brown adipose tissue activity and was fully reversed by housing the mice at thermoneutrality. SIRT1 did not influence brown adipocyte differentiation, but dramatically enhanced the metabolic transcriptional responses to β3-adrenergic stimuli in differentiated adipocytes.
  
  
  CONCLUSIONS
  Our work demonstrates that SIRT1 improves glucose homeostasis by enhancing BAT function. This is not consequent to an alteration in the brown adipocyte differentiation process, but as a result of potentiating the response to β3-adrenergic stimuli.
authors: Nestlé Institute of Health Sciences (NIHS) SA, EPFL Campus, Quartier de l'Innovation, Bâtiment G, Lausanne CH-1015, Switzerland.
authors: Marie
authors: M
authors: Boutant
authors: Nestlé Institute of Health Sciences (NIHS) SA, EPFL Campus, Quartier de l'Innovation, Bâtiment G, Lausanne CH-1015, Switzerland.
authors: Magali
authors: M
authors: Joffraud
authors: Nestlé Institute of Health Sciences (NIHS) SA, EPFL Campus, Quartier de l'Innovation, Bâtiment G, Lausanne CH-1015, Switzerland.
authors: Sameer S
authors: SS
authors: Kulkarni
authors: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain ; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28029 Madrid, Spain.
authors: Ester
authors: E
authors: García-Casarrubios
authors: Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28029 Madrid, Spain ; Diabetes and Obesity Research Laboratory, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona 08036, Spain.
authors: Pablo M
authors: PM
authors: García-Roves
authors: Nestlé Institute of Health Sciences (NIHS) SA, EPFL Campus, Quartier de l'Innovation, Bâtiment G, Lausanne CH-1015, Switzerland ; Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
authors: Joanna
authors: J
authors: Ratajczak
authors: Spanish National Cancer Research Center (CNIO), Madrid E28029, Spain.
authors: Pablo J
authors: PJ
authors: Fernández-Marcos
authors: Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), 28029 Madrid, Spain ; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), 28029 Madrid, Spain.
authors: Angela M
authors: AM
authors: Valverde
authors: Spanish National Cancer Research Center (CNIO), Madrid E28029, Spain.
authors: Manuel
authors: M
authors: Serrano
authors: Nestlé Institute of Health Sciences (NIHS) SA, EPFL Campus, Quartier de l'Innovation, Bâtiment G, Lausanne CH-1015, Switzerland.
authors: Carles
authors: C
authors: Cantó
keywords: Brown adipose tissue; Energy homeostasis; Insulin resistance; SIRT1