UCP1 deficiency increases adipose tissue monounsaturated fatty acid synthesis and trafficking to the liver

James M Ntambi,Laura M Bond

doi:10.1194/jlr.m078469

Abstract

Uncoupling protein-1 (UCP1) facilitates thermogenesis in brown and beige adipocytes and can promote energy expenditure by decreasing mitochondrial respiratory efficiency. Defects in UCP1 and brown adipose tissue thermogenesis subject animals to chronic cold stress and elicit compensatory responses to generate heat. How UCP1 regulates white adipose tissue (WAT) lipid biology and tissue crosstalk is not completely understood. Here, we probed the effect of UCP1 deficiency on FA metabolism in inguinal and epididymal WAT and investigated how these metabolic perturbations influence hepatic lipid homeostasis. We report that at standard housing temperature (21°C), loss of UCP1 induces inguinal WAT de novo lipogenesis through transcriptional activation of the lipogenic gene program and elevated GLUT4. Inguinal adipocyte hyperplasia and depot expansion accompany the increase in lipid synthesis. We also found that UCP1 deficiency elevates adipose stearoyl-CoA desaturase gene expression, and increased inguinal WAT lipolysis supports the transport of adipose-derived palmitoleate (16:1n7) to the liver and hepatic triglyceride accumulation. The observed WAT and liver phenotypes were resolved by housing animals at thermoneutral housing (30°C). These data illustrate depot-specific responses to impaired BAT thermogenesis and communication between WAT and liver in UCP1-/- mice.

Highlights

Uncoupling protein-1 (UCP1) facilitates thermogenesis in brown and beige adipocytes and can promote energy expenditure by decreasing mitochondrial respiratory efficiency
We demonstrated that loss of UCP1 dramatically alters lipid homeostasis in white adipose tissue at the level of gene transcription and substrate flux, inducing FA synthesis and promoting inguinal adipocyte hyperplasia and depot expansion
We identified a 39-nucleotide deletion in the transcript of Ucp1 that occurred at the beginning of exon 5 (Fig. 1A). Quantitative reverse-transcriptase PCR (qPCR) analysis of exon 5 of Ucp1 mRNA confirmed deletion of the cDNA region in all mutant animals (Fig. 1A and supplemental Fig. S1B)

Summary

Introduction

Uncoupling protein-1 (UCP1) facilitates thermogenesis in brown and beige adipocytes and can promote energy expenditure by decreasing mitochondrial respiratory efficiency. Loss of UCP1 surprisingly protects mice against high-fat diet-induced obesity at standard housing temperatures (20–26°C) [12]. Their protection may stem from compensatory mechanisms of thermogenesis in skeletal muscle and adipose tissue [13,14,15,16,17]. A follow-up study reported that, when housed at thermoneutrality (30°C), UCP1 / mice become obese with high-fat diet feeding [18] Together, these studies illustrate that the phenotype of UCP1 / mice depends greatly on the temperature in which they are housed and that chronic cold stress, and subsequently increased circulating norepinephrine [13], elicits a profound global response in these mice

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