title: Stress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis.
abstract: BACKGROUND
  Stress-associated conditions such as psychoemotional reactivity and depression have been paradoxically linked to either weight gain or weight loss. This bi-directional effect of stress is not understood at the functional level. Here we tested the hypothesis that pre-stress level of adaptive thermogenesis and brown adipose tissue (BAT) functions explain the vulnerability or resilience to stress-induced obesity.
  
  
  METHODS
  We used wt and triple β1,β2,β3-Adrenergic Receptors knockout (β-less) mice exposed to a model of chronic subordination stress (CSS) at either room temperature (22 °C) or murine thermoneutrality (30 °C). A combined behavioral, physiological, molecular, and immunohistochemical analysis was conducted to determine stress-induced modulation of energy balance and BAT structure and function. Immortalized brown adipocytes were used for in vitro assays.
  
  
  RESULTS
  Departing from our initial observation that βARs are dispensable for cold-induced BAT browning, we demonstrated that under physiological conditions promoting low adaptive thermogenesis and BAT activity (e.g. thermoneutrality or genetic deletion of the βARs), exposure to CSS acted as a stimulus for BAT activation and thermogenesis, resulting in resistance to diet-induced obesity despite the presence of hyperphagia. Conversely, in wt mice acclimatized to room temperature, and therefore characterized by sustained BAT function, exposure to CSS increased vulnerability to obesity. Exposure to CSS enhanced the sympathetic innervation of BAT in wt acclimatized to thermoneutrality and in β-less mice. Despite increased sympathetic innervation suggesting adrenergic-mediated browning, norepinephrine did not promote browning in βARs knockout brown adipocytes, which led us to identify an alternative sympathetic/brown adipocytes purinergic pathway in the BAT. This pathway is downregulated under conditions of low adaptive thermogenesis requirements, is induced by stress, and elicits activation of UCP1 in wt and β-less brown adipocytes. Importantly, this purinergic pathway is conserved in human BAT.
  
  
  CONCLUSIONS
  Our findings demonstrate that thermogenesis and BAT function are determinant of the resilience or vulnerability to stress-induced obesity. Our data support a model in which adrenergic and purinergic pathways exert complementary/synergistic functions in BAT, thus suggesting an alternative to βARs agonists for the activation of human BAT.
authors: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Maria
authors: M
authors: Razzoli
authors: Department of Experimental and Clinical Medicine, Center for Obesity, Università Politecnica delle Marche, Ancona 60020, Italy.
authors: Andrea
authors: A
authors: Frontini
authors: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Allison
authors: A
authors: Gurney
authors: Department of Experimental and Clinical Medicine, Center for Obesity, Università Politecnica delle Marche, Ancona 60020, Italy.
authors: Eleonora
authors: E
authors: Mondini
authors: Computational Genomics Department, Centro de Investigación Príncipe Felipe, C/ Eduardo Primo Yufera 3, 46012 Valencia, Spain.
authors: Cankut
authors: C
authors: Cubuk
authors: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors: Liora S
authors: LS
authors: Katz
authors: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Cheryl
authors: C
authors: Cero
authors: Department of Radiology and Center for Magnetic Resonance Research, University of Minnesota, MN 55455, USA.
authors: Patrick J
authors: PJ
authors: Bolan
authors: Computational Genomics Department, Centro de Investigación Príncipe Felipe, C/ Eduardo Primo Yufera 3, 46012 Valencia, Spain.
authors: Joaquin
authors: J
authors: Dopazo
authors: University of Cambridge Metabolic Research Laboratories, Cambridge CB2 OQQ, UK; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
authors: Antonio
authors: A
authors: Vidal-Puig
authors: Department of Experimental and Clinical Medicine, Center for Obesity, Università Politecnica delle Marche, Ancona 60020, Italy.
authors: Saverio
authors: S
authors: Cinti
authors: Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Alessandro
authors: A
authors: Bartolomucci
keywords: Energy expenditure; P2RX5; Purinergic; Subordinate; UCP1