Stress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis.

TitleStress-induced activation of brown adipose tissue prevents obesity in conditions of low adaptive thermogenesis.
Publication TypeJournal Article
Year of Publication2016
AuthorsRazzoli, M, Frontini, A, Gurney, A, Mondini, E, Cubuk, C, Katz, LS, Cero, C, Bolan, PJ, Dopazo, J, Vidal-Puig, A, Cinti, S, Bartolomucci, A
JournalMol Metab
Date Published2016 Jan

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.CONCLUSION: 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.

Alternate JournalMol Metab
PubMed ID26844204
PubMed Central IDPMC4703853
Grant ListMC_G0802535 / / Medical Research Council / United Kingdom
PG/12/53/29714 / / British Heart Foundation / United Kingdom
P41 EB015894 / EB / NIBIB NIH HHS / United States
MC_UU_12012/2 / / Medical Research Council / United Kingdom
R01 DK102496 / DK / NIDDK NIH HHS / United States
R01 AG043972 / AG / NIA NIH HHS / United States