CD36 is indispensable for thermogenesis under conditions of fasting and cold stress

https://doi.org/10.1016/j.bbrc.2014.12.124Get rights and content

Highlights

  • We examined the role of CD36 in thermogenesis during cold exposure.

  • CD36−/− mice exhibit rapid hypothermia after cold exposure during fasting.

  • Uptake of fatty acid and glucose is impaired in thermogenic tissues during fasting.

  • Storage of energy substrates is reduced in thermogenic tissues during fasting.

  • CD36 is important for nutrient homeostasis to survive life-threatening challenges.

Abstract

Hypothermia can occur during fasting when thermoregulatory mechanisms, involving fatty acid (FA) utilization, are disturbed. CD36/FA translocase is a membrane protein which facilitates membrane transport of long-chain FA in the FA consuming heart, skeletal muscle (SkM) and adipose tissues. It also accelerates uptake of triglyceride-rich lipoprotein by brown adipose tissue (BAT) in a cold environment. In mice deficient for CD36 (CD36−/− mice), FA uptake is markedly reduced with a compensatory increase in glucose uptake in the heart and SkM, resulting in lower levels of blood glucose especially during fasting. However, the role of CD36 in thermogenic activity during fasting remains to be determined. In fasted CD36−/− mice, body temperature drastically decreased shortly after cold exposure. The hypothermia was accompanied by a marked reduction in blood glucose and in stores of triacylglycerols in BAT and of glycogen in glycolytic SkM. Biodistribution analysis using the FA analogue 125I-BMIPP and the glucose analogue 18F-FDG revealed that uptake of FA and glucose was severely impaired in BAT and glycolytic SkM in cold-exposed CD36−/− mice. Further, induction of the genes of thermogenesis in BAT was blunted in fasted CD36−/− mice after cold exposure. These findings strongly suggest that CD36−/− mice exhibit pronounced hypothermia after fasting due to depletion of energy storage in BAT and glycolytic SkM and to reduced supply of energy substrates to these tissues. Our study underscores the importance of CD36 for nutrient homeostasis to survive potentially life-threatening challenges, such as cold and starvation.

Introduction

In a cold environment, thermoregulatory heat production is increased by either non-shivering thermogenesis (NST), shivering thermogenesis, or physical activity. Among these, NST in brown adipose tissue (BAT) is the most important thermoregulatory mechanism in small mammals and human neonates [1], [2]. BAT dissipates chemical energy and generates heat to help protect animals from cold temperatures. Upon stimulation by sympathetic nervous input, cellular triglyceride (TG) stores undergo lipolysis and in BAT the thermogenic regulator peroxisome proliferator-activated receptor gamma co-activator 1α (PGC1α) is induced [1], [2], [3]. For sustaining heat production in BAT, efficient uptake and subsequent utilization of fuels such as glucose and FA are required [4]. Thermogenesis in BAT is mediated through the BAT-specific mitochondrial protein, uncoupling protein 1 (UCP1) [1], [2]. Skeletal muscle (SkM) is another crucial tissue for generating heat by shivering and physical activity. Shivering muscles are largely fueled by carbohydrates and lipids [5]. Although the contribution of circulating glucose to total heat generation remains minor (<15% of total heat produced), muscle glycogen becomes the dominant fuel, providing 30–40% of the total heat produced or 75% of the total carbohydrate oxidized [6].

CD36 plays an important role in membrane transport of long-chain FA in the heart, SkM and adipose tissue [7]. The expression of CD36 is increased by cold exposure, which enhances BAT uptake of TG-rich lipoprotein (TRL) and of albumin bound FA [8], [9]. Increased activity of local lipoprotein lipase (LPL) accelerates hydrolysis of TG within TRL, followed by efficient engulfment of lipoprotein particles by BAT. Previous studied showed that CD36−/− mice have reduced uptake of FA with a remarkable increase in glucose utilization in the heart and oxidative SkM, lower levels of blood glucose and higher levels of serum NEFAs [10], [11] (and our unpublished observation). Compared with oxidative SkM, uptake of FA in glycolytic SkM is less affected while uptake of glucose is marginally enhanced.

In this study, we examined the role of CD36 in thermogenesis in response to cold exposure during fasting. Using CD36−/− and wild-type (WT) mice, we document the indispensable role of CD36 for tolerance of cold temperature when nutrient supply is limited. Most energy substrates for thermogenesis, such as TG in BAT and glycogen in glycolytic SkM are rapidly consumed in the fasted state and mechanisms replenishing these energy substrates fail in CD36−/− mice, resulting in rapid occurrence of fatal hypothermia upon cold exposure.

Section snippets

Mice and sample collection

Mice with a homozygous null mutation in CD36 were generated as previously described [12]. Control male wild-type C57BL6j mice were purchased from Japan SLC, Inc. The ages (10–12 weeks) and body weights (22–27 g) of WT and CD36−/− mice were comparable for all experiments. All study protocols were approved by The Institutional Animal Care and Use Committee (Gunma University Graduate School of Medicine). The mice were housed in a temperature-controlled room (22 C) in a 12-h light/12-h dark cycle

Effects of cold stress on body temperature in fed and fasted mice

To determine the effects of cold stress, wild-type (WT) and CD36−/− mice were exposed to a cold environment (4 °C) for 2 h with or without prior fasting for 20 h (Fig. 1). The body surface temperature was comparable between WT and CD36−/− mice without prior fasting (Fig. 1A). However, the body temperature of all CD36−/− mice that were fasted for 20 h rapidly declined and reached below 25 °C within 2 h of cold exposure (Fig. 1B). In contrast, the body temperature of WT mice was higher than 30 °C

Discussion

In this study, we demonstrate an indispensable role of CD36 in thermogenesis when cold exposure is combined with a prior fast. During fasting, glucose utilization continues to be enhanced in the heart and oxidative SkM of CD36−/− mice leading to accelerated hypoglycemia. Further, uptake of glucose in addition to the impaired FA uptake, were severely affected in thermogenic tissues such as BAT and glycolytic SkM of CD36−/− mice upon brief cold exposure. Consequently, CD36−/− mice displayed

Conflict of interest

None.

Acknowledgments

We thank Miki Matsui, Yukiyo Tosaka, Keiko Matsukura and Takako Kobayashi for excellent technical help. This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the promotion of Science, to T.I. (26461123), to M.K. (24390194). a grant from the Japan Cardiovascular Foundation (to MK) and a grant from the Vehicle Racing Commemorative Foundation and (to TI).

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    These authors contributed equally to this work.

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