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Abstract
Sympathetic nervous system (SNS) innervation into brown adipose tissue (BAT) has been viewed as an impetus for brown fat thermogenesis. However, we surprisingly discovered that BAT SNS innervation is dispensable for mice to maintain proper body temperature during a prolonged cold exposure. Here we aimed to uncover the physiological factors compensating for maintaining brown fat thermogenesis in the absence of BAT innervation. After an initial decline of body temperature during cold exposure, mice with SNS surgical denervation in interscapular BAT gradually recovered their temperature comparable to that of sham-operated mice. The surgically denervated BAT also maintained a sizable uncoupling protein 1 (UCP1) protein along with basal norepinephrine (NE) at a similar level to that of sham controls, which were associated with increased circulating NE. Furthermore, the denervated mice exhibited increased free fatty acid levels in circulation. Indeed, surgical denervation of mice with CGI-58 deletion in adipocytes, a model lacking lipolytic capacity to release fatty acids from WAT, dramatically reduced BAT UCP1 protein and rendered the mice susceptible to cold. We conclude that circulating fatty acids and NE may serve as key factors for maintaining BAT thermogenic function and body temperature in the absence of BAT sympathetic innervation.
Highlights
Obesity poses a serious risk for the development of a panel of metabolic diseases that greatly increase morbidity and mortality in current society [1]
The premise of this study was derived from our prior observations on the hamsters with interscapular BAT (iBAT) Sympathetic nervous system (SNS) denervation [20]
Thermogenesis, hamsters lacking iBAT SNS innervation with chemical SNS denervation were viable and displayed a normal core temperature when challenged with cold at 4 ◦ C. These animals benefited from an induction of beige adipocytes due to enhanced SNS innervation into inguinal WATmice (iWAT), which offsets the loss of iBAT thermogenesis [20]
Summary
Obesity poses a serious risk for the development of a panel of metabolic diseases that greatly increase morbidity and mortality in current society [1]. While white adipose tissue (WAT) stores excess energy in the form of triglyceride, brown adipose tissue (BAT) dissipates energy through adaptive thermogenesis via UCP1, a mitochondrial inner membrane protein that uncouples oxidative phosphorylation from. One is the classic brown fat that is confined to anatomically defined regions such as interscapular BAT (iBAT) and the other are inducible beige adipocytes that reside sporadically within WAT and can be induced by cold, β-adrenergic agonists, PPARγ agonists, myokines (e.g., irisin) and hepatokines (e.g., FGF21) [2,3,4,5,6]. Given the recent insights into the functional BAT in humans [11,12,13], activation of brown/beige adipocyte thermogenesis represents a promising strategy for therapeutic treatment of obesity
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