Calsyntenin 3β Is Dynamically Regulated by Temperature in Murine Brown Adipose and Marks Human Multilocular Fat.

Kaja Plucińska,Erin L Brown,Brice Emanuelli,Patricia S Petersen,Søren Nielsen,Camilla Scheele,Naja Z Jespersen,Kaja Rupar

doi:10.3389/fendo.2020.579785

Abstract

Activation of thermogenic adipose tissue is linked to improved metabolic outcomes in mice and humans. Dissipation of energy as heat during thermogenesis relies on sufficient innervation of fat by sympathetic nerve fibers, a process recently proposed to be regulated by the adipose-specific calsyntenin3β (Clstn3β)-S100b axis. Here we aimed 1) to assess enrichment patterns of CLSTN3β, S100b as well as the previously annotated neuronal CLSTN3α in perirenal brown and subcutaneous white human fat specimens, and 2) to investigate if the novel Clstn3β is dynamically regulated by changes in environmental temperatures and nutritional stress in thermogenic adipose tissues in mice. We provide evidence for CLSTN3β enrichment in multilocular perirenal fat located anatomically in the proximity to both the adrenal gland and sympathetic nerve bundles innervating the kidney in humans. Moreover, transcript levels of CLSTN3β, but not S100b or CLSTN3α, positively correlate with uncoupling protein 1 (UCP1) expression in human adipose tissue. Our results further show that Clsnt3β is preferentially expressed in brown adipocytes and is highly responsive to changes in environmental temperature and obesity state in mice. Collectively, this brief communication highlights CLSTN3β as a hallmark of thermogenic adipose depots in mice and humans.

Highlights

Cold-induced activation of brown (BAT) and beige adipose tissues enable non-shivering thermogenesis via oxidation of substrates [1], a process dependent on the sympathetic innervation of fat
We observed a pronounced enrichment of calsyntenin 3b (Clstn3b) transcripts in BAT compared to white adipose tissue (WAT) depots (p < 0.001), where Clstn3b expression was 90% lower in SAT and visceral adipose tissue (VAT) at 29°C
The neurotrophic partner of Clstn3b, S100b was not enriched in any particular fat depot but its expression was altered by cold in a depot-specific manner

Summary

Introduction

Cold-induced activation of brown (BAT) and beige adipose tissues enable non-shivering thermogenesis via oxidation of substrates [1], a process dependent on the sympathetic innervation of fat. Deep neck BAT volume inversely correlates with body mass index in healthy individuals [2] and its activation via short-term cold acclimation increases insulin sensitivity in patients with type II diabetes [3]. Calsyntenin 3b Expression in Thermogenic Fat. Sympathetic innervation of fat by adrenergic neurons is indispensable for norepinephrine (NE)-stimulated lipolysis and activation of uncoupling protein 1 (UCP1) [4, 5], as demonstrated by chemical or surgical denervation of fat [6, 7]. S100b was recently shown to be regulated by a previously unknown adipose-specific calsyntenin 3b (Clstn3b) molecule

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Results

Conclusion