Adaptive adipose tissue stromal plasticity in response to cold stress and antibody-based metabolic therapy

Millicent Lin ,Beatrice Breart,Lance Kates,Sairupa Paduchuri,Zora Modrušan ,Isabelle Lehoux,Junichiro Sonoda,Andrew S Peterson,Matthew B Buechler,Jingli A Zhang,Shannon J Turley,Joshua C Chang,Travis W Bainbridge,Alessandra Castiglioni,Nadia Martínez‐Martín ,Mark Z Chen,Steffen Durinck,Margaret Solon,James A Ernst,Sree R Ramani,Jianguo Wu ,Minh Thai,Hong Li

doi:10.1038/s41598-019-45354-1

Millicent Lin , Beatrice Breart + Show 21 more

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https://doi.org/10.1038/s41598-019-45354-1

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Journal: Scientific Reports	Publication Date: Jun 20, 2019
Citations: 11	License type: open-access

Affiliation: Regeneron (United States)

Abstract

In response to environmental and nutrient stress, adipose tissues must establish a new homeostatic state. Here we show that cold exposure of obese mice triggers an adaptive tissue remodeling in visceral adipose tissue (VAT) that involves extracellular matrix deposition, angiogenesis, sympathetic innervation, and adipose tissue browning. Obese VAT is predominated by pro-inflammatory M1 macrophages; cold exposure induces an M1-to-M2 shift in macrophage composition and dramatic changes in macrophage gene expression in both M1 and M2 macrophages. Antibody-mediated CSF1R blocking prevented the cold-induced recruitment of adipose tissue M2 macrophages, suggesting the role of CSF1R signaling in the process. These cold-induced effects in obese VAT are phenocopied by an administration of the FGF21-mimetic antibody, consistent with its action to stimulate sympathetic nerves. Collectively, these studies illuminate adaptive visceral adipose tissue plasticity in obese mice in response to cold stress and antibody-based metabolic therapy.

Highlights

In response to environmental and nutrient stress, adipose tissues must establish a new homeostatic state
Adipose tissue browning characterized by the emergence of UCP1+ multilocular adipocytes and increased UCP1 protein expression by western blot was observed in subcutaneous adipose tissue (SCAT), but not in visceral adipose tissue (VAT) in the lean animals (Fig. 1C,D)
We believe that the cold-induced sympathetic stimulation in the obese VAT has significant metabolic consequences, the modest induction of UCP1-positive beige adipocytes in VAT is unlikely sufficient to contribute much to overall thermal defense or whole-body energy metabolism

Summary

Introduction

In response to environmental and nutrient stress, adipose tissues must establish a new homeostatic state. Adipose tissues are under the neural control of the sympathetic nervous system (SNS), mediated by tyrosine hydroxylase (TH)-positive catecholaminergic neurons that innervate from the paravertebral sympathetic ganglia into adipose tissues[15,16,17] Physiological stress such as cold exposure stimulates sympathetic nerves to release catecholamine, which activates adrenergic receptors expressed in adipocytes and stromal cells to trigger lipolysis, adaptive thermogenesis, and white adipose browning[15,17,18]. Www.nature.com/scientificreports adipose browning is generally absent in healthy VAT in lean mice[23,26], which could be attributed to a scarcity of sympathetic nerve fibers and lesser cold-induced SNS drive in this tissue[19,30] These studies overall implicated a therapeutic SNS stimulation in the treatment of obesity-associated insulin resistance; the consequence of the SNS stimulation in VAT microenvironment in obese animals is poorly understood, motivating us to interrogate the effect of cold-exposure and a drug-induced SNS stimulation in obese VAT phenotype. We describe a dynamic visceral adipose tissue stromal remodeling in response to the SNS stimulation, that involves adipose tissue macrophages

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