Chronic high-fat feeding impairs adaptive induction of mitochondrial fatty acid combustion-associated proteins in brown adipose tissue of mice

Takayuki Ohtomo,Kanako Ino,Ryota Miyashita,Maya Chigira,Masahiko Nakamura,Koji Someya,Niro Inaba,Mariko Fujita,Mitsuhiro Takagi,Junji Yamada

doi:10.1016/j.bbrep.2017.02.002

Takayuki Ohtomo, Kanako Ino + Show 8 more

Open Access

https://doi.org/10.1016/j.bbrep.2017.02.002

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Abstract

Since brown adipose tissue (BAT) is involved in thermogenesis using fatty acids as a fuel, BAT activation is a potential strategy for treating obesity and diabetes. However, whether BAT fatty acid combusting capacity is preserved in these conditions has remained unclear. We therefore evaluated expression levels of fatty acid oxidation-associated enzymes and uncoupling protein 1 (Ucp1) in BAT by western blot using a diet-induced obesity C57BL/6J mouse model. In C57BL/6J mice fed a high-fat diet (HFD) over 2–4 weeks, carnitine palmitoyltransferase 2 (Cpt2), acyl-CoA thioesterase (Acot) 2, Acot11 and Ucp1 levels were significantly increased compared with baseline and control low-fat diet (LFD)-fed mice. Similar results were obtained in other mouse strains, including ddY, ICR and KK-Ay, but the magnitudes of the increase in Ucp1 level were much smaller than in C57BL/6J mice, with decreased Acot11 levels after HFD-feeding. In C57BL/6J mice, increased levels of these mitochondrial proteins declined to near baseline levels after a longer-term HFD-feeding (20 weeks), concurrent with the accumulation of unilocular, large lipid droplets in brown adipocytes. Extramitochondrial Acot11 and acyl-CoA oxidase remained elevated. Treatment of mice with Wy-14,643 also increased these proteins, but was less effective than 4 week-HFD, suggesting that mechanisms other than peroxisome proliferator-activated receptor α were also involved in the upregulation. These results suggest that BAT enhances its fatty acid combusting capacity in response to fat overload, however profound obesity deprives BAT of the responsiveness to fat, possibly via mitochondrial alteration.

Highlights

Adult mammals have at least two types of adipocytes in the body: white adipocytes that accumulate fat as a triglyceride (TG) in cells in preparation for starvation, and brown adipocytes that combust fat to maintain body temperature
We examined the changes in fatty acid combusting capacity by measuring protein expression levels of fatty acid oxidationassociated enzymes, including carnitine palmitoyltransferase 2 (Cpt2), acyl-CoA thioesterase 2 (Acot2), Acot11 and acyl-CoA oxidase 1 (Acox1), as well as uncoupling protein 1 (Ucp1) and peroxisome proliferator-activated receptor (Ppar) γ in brown adipose tissue (BAT), using a diet-induced obesity mouse model established by high-fat diet (HFD)-feeding
Similar results were obtained for Cpt2, Acot2 and Ucp1 in BAT of ddY, ICR and genetically diabetic KK-Ay mice, the extent of increase in the protein levels varied among mouse strains, with the most consistent induction observed in C57BL/6J mice (Fig. 1)

Summary

Introduction

Adult mammals have at least two types of adipocytes in the body: white adipocytes that accumulate fat as a triglyceride (TG) in cells in preparation for starvation, and brown adipocytes that combust fat to maintain body temperature. Brown adipocytes possess a high density of mitochondria in which energy derived from fatty acid degradation is dissipated as heat by the action of uncoupling protein 1 (Ucp1), which is exclusively expressed in this cell type [1]. For this reason, activation of brown adipocytes leads to an increase in calorie consumption and is expected to improve overweight conditions, providing a potential strategy for treating obesity and its related metabolic disorders [1,2,3,4,5]. Whether BAT fatty acid combusting capacity is preserved in obese and diabetic conditions remains unclear

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