Lose Weight by Eating Less? Academia Sinica Research Team Discovers a Novel Regulatory Mechanism for Burning Fat by Promoting Thermogenesis in Brown Adipose Tissue
Weight loss is not merely a matter of diet, but also involves burning excess fat. A research team consisting of Dr. Yi-Shuian Huang and colleagues at the Institute of Biomedical Sciences, Academia Sinica, has discovered a CPEB2-controlled mechanism for promoting the synthesis of thermogenic UCP1 protein in brown adipose tissue, thereby increasing heat production and energy expenditure. Their results were published in the September 3, 2018 issue of EMBO J., with Institute of Biomedical Sciences Postdoctoral Research Fellow Hui Feng Chen being first author and Research Assistant Chen-Ming Hsu the second author.
Obesity and obesity-induced diseases have become a global health crisis. Although the idea of keeping fit by balancing one’s energy intake and consumption sounds simple enough, people’s sedentary life style, voracious appetite and accessible high-fat foods have combined to spark an obesity epidemic. Dietary restrictions and exercise have not always proven effective in combatting obesity because most people cannot persist in these efforts for the long term. Thus, scholars have become increasingly interested in increasing basal metabolic rates to burn excess fat.
The expression of the mitochondrial proton transporter uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is essential for mammalian thermogenesis. Previous studies in mice with genetic ablations of BAT or UCP1 showed that UCP1-mediated BAT thermogenesis is essential for managing body weight. The discovery of BAT in human adults whose metabolic activity is correlated positively with resting metabolic rates but negatively with body mass index and body fat has made it clear that increasing BAT metabolism might be a promising therapeutic tool to combat obesity and related metabolic diseases. While human UCP1 mRNA only exists in a long form, alternative polyadenylation creates two different isoforms in mice with 10% of UCP1 mRNA found in the long form (Ucp1L) and ~90% in the short form (Ucp1S). To address whether these two kinds of Ucp1 transcripts produce UCP1 protein (a process called “translation”) with differing degrees of efficiency, we generated a mouse model expressing only Ucp1S, and found that it reduced heat production due to a ~60% drop in UCP1 protein levels, which suggests that Ucp1L is more efficiently translated than Ucp1S. We further identified that the signaling of the cytoplasmic polyadenylation element binding protein 2 (CPEB2) through b3 adrenergic receptors promoted the translation of mouse Ucp1L and human Ucp1 in cultured brown adipocytes. CPEB2-knockout mice showed reduced UCP1 levels and impaired thermogenesis in BAT, which could be remedied by ectopic expressions of CPEB2, thereby supporting the essential role of CPEB2 in BAT metabolism.
Nutrient uptake and cold temperatures stimulate BAT thermogenesis via the control of sympathetic circuits to activate β3 adrenergic receptor signaling and consequently increase UCP1 expression. As noted above, using food restriction to control obesity is largely ineffective because most people are unable to resist the temptation to eat rich food. Moreover, diet is a potent regulator of adaptive thermogenesis, so starvation can decrease resting metabolic rates. Such a counter-productive metabolic adaptation likely contributes significantly to the poor long-term efficacy of dietary treatments. Mice lacking CPEB2 or Ucp1L mRNA showed reduced levels of UCP1 protein and impaired thermogenesis, supporting the view that regulated translation efficiency of Ucp1L mRNA by CPEB2 in BAT plays a critical role in “upping” thermogenesis. We think this regulatory mechanism may be more important in humans due to their expression of long Ucp1 mRNA only. CPEB2-controlled translation in BAT regulates body weight in mice, but whether it can prove significant for weight management and metabolic fitness in humans requires further investigation. If so, up-expressions of CPEB2 in BAT may provide a means of combatting obesity.
Dr. Yi-Shuian Huang, Institute of Biomedical Sciences, Academia Sinica
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Mr. Chang-Hung Chen, Secretariat Office, Central Office of Administration,
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Mr. Chung-Hui Chuang, Secretariat Office, Central Office of Administration,
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