Melatonin Regulates Differentiation of Sheep Brown Adipocyte Precursor Cells Via AMP-Activated Protein Kinase.

Xu-Yang Gao,Xin-Rui Li,Yu Wang,Jun-Xing Zhao,Xiao-Yan Hao,Jian-Xin Zhang,Bu-Hao Deng

doi:10.3389/fvets.2021.661773

Xu-Yang Gao, Xin-Rui Li + Show 5 more

Open Access

https://doi.org/10.3389/fvets.2021.661773

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Abstract

In sheep industry, hypothermia caused by insufficient brown adipose tissue (BAT) deposits is one of the major causes of lamb deaths. Enhancing the formation and function of BAT in neonatal lamb increases thermogenesis and hence reduces economic losses. The aim of the present study was to explore the effect and mechanism of melatonin on sheep brown adipocyte formation and function. Sheep brown adipocyte precursor cells (SBACs) isolated from perirenal BAT were treated with melatonin (1 and 10 nM). The SBACs subjected to melatonin exhibited a decreased proliferation ability, accompanied by down-regulated proliferating cell nuclear antigen, cyclin D1, and CDK4 protein contents in a melatonin dose-dependent manner. Melatonin promoted brown adipocyte formation and induced the expression of brown adipogenic markers, including uncoupling protein 1 and PR domain-containing 16 during differentiation of SBAC. Moreover, the AMP-activated protein kinase α1 (AMPKα1) activity was positively correlated with brown adipocyte formation potential. Importantly, melatonin effectively activated AMPKα1. Furthermore, promotional effects of melatonin were abolished by AMPKα1 knockout, suggesting the involvement of AMPKα1 in this process. Collectively, these results suggested that melatonin enhanced brown adipocyte formation in SBACs in vitro through activation of AMPKα1.

Highlights

Mammalian brown adipose tissue (BAT) is responsible for metabolic heat generation through nonshivering thermogenesis, which is due to the high contents of uncoupling protein-1 (UCP1) and mitochondria [1]
Considering that heat production by BAT accounts for approximately half of the heat needed by newborn lambs to maintain central temperature [4], the BAT is essential for the survival of newborns, especially for those born in a cold winter
Disinfected BAT pieces were minced with scissors and digested in a Abbreviations: BAT, brown adipose tissue; PCNA, proliferation cell nuclear antigen; CDK4, cyclin-dependent kinase 4; AMPKα1, 5′-adenosine monophosphate-activated protein kinase; p-AMPKα1, phospho-5′-adenosine monophosphate-activated protein kinase; UCP1, uncoupling protein 1; PRDM16, PR domain containing 16; C/EBPβ, CCAAT-enhancer–binding protein beta; complex III, coenzyme Q-cytochrome c reductase; complex V, ATP synthase; KO, knockout; PGC1α, peroxisome proliferator-activated receptor-γ coactivator; cell death-inducing DNA fragmentation factor-α-like effector A (Cidea), cell death–inducing DNA fragmentation factor-α-like effector A; Cox7a, cytochrome c oxidase polypeptide 7a; ACC, acetyl-CoA carboxylase; p-ACC, phospho-acetyl-CoA carboxylase

Summary

Introduction

Mammalian brown adipose tissue (BAT) is responsible for metabolic heat generation through nonshivering thermogenesis, which is due to the high contents of uncoupling protein-1 (UCP1) and mitochondria [1]. It is well-established that BAT plays an important role in mammalian thermoregulatory responses to a cold environment. Considering that heat production by BAT accounts for approximately half of the heat needed by newborn lambs to maintain central temperature [4], the BAT is essential for the survival of newborns, especially for those born in a cold winter. Exploring the underlying mechanisms regulating BAT development and function is important for sheep production and welfare.

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