Biochemical and Biophysical Research Communications
CD36 is indispensable for thermogenesis under conditions of fasting and cold stress
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in the heart and oxidative SkM, lower levels of blood glucose and higher levels of serum NEFAs [10], [11] (and our unpublished observation).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).
References (25)
- et al.
Defective uptake and utilization of long chain fatty acids in muscle and adipose tissues of CD36 knockout mice
J. Biol. Chem.
(2000) - et al.
A null mutation in murine CD36 reveals an important role in fatty acid and lipoprotein metabolism
J. Biol. Chem.
(1999) - et al.
CD36 deficiency associated with insulin resistance
Lancet
(2001) - et al.
Cellular fatty acid uptake: a pathway under construction
Trends Endocrinol. Metab.
(2009) - et al.
CD36 protein influences myocardial Ca2+ homeostasis and phospholipid metabolism: conduction anomalies in CD36-deficient mice during fasting
J. Biol. Chem.
(2012) - et al.
Brown adipose tissue: function and physiological significance
Physiol. Rev.
(2004) Cold-induced recruitment of brown adipose tissue thermogenesis
Exp. Physiol.
(2003)- et al.
Control of Brown Adipose Tissue Glucose and Lipid Metabolism by PPARgamma
(2011) - et al.
Fatty acid binding protein 4 and 5 play a crucial role in thermogenesis under the conditions of fasting and cold stress
PLoS One
(2014) Shivering in the cold: from mechanisms of fuel selection to survival
J. Appl. Physiol.
(2006)
Partitioning oxidative fuels during cold exposure in humans: muscle glycogen becomes dominant as shivering intensifies
J. Physiol.
Membrane fatty acid transporters as regulators of lipid metabolism: implications for metabolic disease
Physiol. Rev.
Cited by (0)
- 1
These authors contributed equally to this work.