Adipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue

Xin Cui,Liqing Yu,Jia Jing,Fenfen Li,Rui Wu,Gary Schwartz,Huidong Shi,Ke Li,Bingzhong Xue,Shirong Wang,Qiang Cao,Hang Shi

doi:10.1038/s41467-021-25766-2

Abstract

Activation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. Here we discover a fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NT-3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. NT-3 is highly expressed in brown/beige adipocytes, and potently stimulates sympathetic neuron neurite growth. NT-3/TRKC regulates a plethora of pathways in neuronal axonal growth and elongation. Adipose tissue sympathetic innervation is significantly increased in mice with adipocyte-specific NT-3 overexpression, but profoundly reduced in mice with TRKC haploinsufficiency (TRKC +/−). Increasing NT-3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC + /− or SNS TRKC deficient mice are cold intolerant and prone to DIO. Thus, NT-3 is a fat-derived neurotrophic factor that regulates SNS innervation, energy metabolism and obesity.

Highlights

Activation of brown fat thermogenesis increases energy expenditure and alleviates obesity
We discovered that the expression of the fat-derived neurotrophic factor neurotrophin 3 (NT-3) is higher in mouse brown adipose tissue (BAT) than white adipose tissue (WAT); NT-3 expression coincides with the appearance of developmentally induced beige adipocytes in postnatal mice and is induced in WAT by cold exposure in adult mice
Xue et al previously found that beige adipocytes can be induced in WAT during cold exposure in adult animals and in newborn pups, which peaked at 20 days of age[11]

Summary

Introduction

Activation of brown fat thermogenesis increases energy expenditure and alleviates obesity. Sympathetic nervous system (SNS) is important in brown/beige adipocyte thermogenesis. We discover a fat-derived “adipokine” neurotrophic factor neurotrophin 3 (NT-3) and its receptor Tropomyosin receptor kinase C (TRKC) as key regulators of SNS growth and innervation in adipose tissue. Increasing NT-3 via pharmacological or genetic approach promotes beige adipocyte development, enhances cold-induced thermogenesis and protects against diet-induced obesity (DIO); whereas TRKC + /− or SNS TRKC deficient mice are cold intolerant and prone to DIO. NT-3 is a fat-derived neurotrophic factor that regulates SNS innervation, energy metabolism and obesity. A recent discovery of metabolically active brown fat in adult humans has further implicated BAT thermogenesis as a promising therapeutic target for the treatment of obesity[8,9,10]. Xue et al previously reported the existence of a unique subset of beige adipocytes, so-called developmentally induced beige adipocytes, which are transiently induced in postnatal mice[11]

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Conclusion