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Fasting induces a miRNA-mediated subcutaneous to visceral fat switch

Nanjing University School of Life Sciences

In a new study published in Nature Communications, Chen-Yu Zhang's group from Nanjing University reports that 24 hours of fasting induces a miRNA-149-3p-mediated subcutaneous to visceral fat switch via suppression of PRDM16 in mice.

As an integrator of energy homeostasis, many basic physiological functions provided by adipose tissue have been overlooked because of their association with obesity. Cold and hunger were probably the baseline states in humans over a substantial portion of evolutionary time. Therefore, the lipid-burning brown/beige adipocytes are specialized to maintain body temperature by producing heat in a cold environment, whereas the lipid-storing white adipocytes are adapted to cope with food shortage. Recently, it has become clear that subcutaneous fat possesses substantial thermogenic capacity in response to cold stimulation compared with visceral depots. This cold-induced emergence of brown-like adipocytes in subcutaneous fat suggests that certain adipose processes are extraordinarily plastic in response to changes in environmental cues. Although several studies have reported that mobilization of the subcutaneous depot appears to be less than that of visceral fat during starvation, an important challenge is to understand the molecular mechanisms by which physiological changes regulate these different white adipose depots.

In the present study, Chen-Yu's group showed that in addition to the capacity of 'browning' to defend against hypothermia during cold exposure, the subcutaneous depot is also capable of 'whitening' to preserve energy during fasting to maintain energy balance, via miR-149-3p-mediated regulation of PRDM16.

This work is important for the following reasons:

1) In this study, they showed that 24-h fasting triggered a depot-specific pattern of changes in both lipogenic and lipolytic genes in mice, indicating preferential mobilization of lipids in visceral depots compared with subcutaneous fat pads. Food deprivation also stimulated a visceral-like switch in subcutaneous depots. These observation may be evolutionarily important. Fasting has been practiced for millennia. During fasting, preferentially oxidized visceral fat can drain directly into the portal circulation and appears to be more efficient at meeting energy needs compared with the relatively externally located subcutaneous fat. Simultaneously, because large amounts of visceral fat are being used, subcutaneous fat must undergo a morphological and functional visceral-like switch to prepare to become a backup energy reservoir.

2) Visceral adiposity is strongly associated with metabolic disease risk, whereas subcutaneous adiposity is comparatively benign. However, their relative physiological importance in energy homeostasis remains unclear. Recent studies demonstrate that the 'browning' of subcutaneous adipose tissue is capable of defending against hypothermia. In this study, using a 24-h fasting stimulus, they found that fasting stimulated a set of visceral gene transcripts but decreased the expression of genes related to the thermogenic programme, presumably to preserve energy. Therefore, cold exposure and fasting, two different physiological stimuli, lead to nearly opposite phenotypic and functional changes in subcutaneous adipocytes to maintain the energy balance. This extraordinary plasticity of subcutaneous depot suggests that this adipose tissue might play even broader roles in the physiology and homeostasis of mammals.

3) Emerging evidence suggests fascinating effects of intermittent fasting. By alternating 24-h cycles of fasting and ad libitum feeding, they found that the visceral fats decreased. However, unlike visceral fat, the decreased weight was restored in subcutaneous depots by 24-h refeeding, suggesting the "visceralization" of subcutaneous fat is an adaptive response to 24-h fasting-induced physiological stress to maintain whole-body energy homeostasis. These results confirmed that alternating day-fasting preferentially consumes the "metabolically harmful" visceral fat, which might benefit health.

4) Recently, the appreciated 'browning' ability of subcutaneous fat, which are capable of defending against hypothermia and obesity, has caused an explosion of interest in the function of this adipose tissue. They showed that during this fast-induced 'visceralization', the upregulated miR-149-3p directly targets PRDM16, a key coregulatory protein required for the 'browning' of white fat. More importantly, they demonstrated that subcutaneous inhibition by anti-miR-149-3p activated beige cell development in inguinal fat and subsequently increased whole-body energy expenditure without causing dysfunction in other tissues, which might be a potential strategy to counteract obesity.

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The researchers of this project include Hanying Ding, Shasha Zheng, Daniel Garcia, Dongxia Hou, Zhe Wei, Zhicong Liao, Limin Li, Yujing Zhang, Xiao Han Ke Zen, Chen-Yu Zhang, Jing Li, Xiaohong Jiang, State Key Laboratory of Pharmaceutical Biotechnology, Collaborative Innovation Center of Chemistry for Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute for Life Sciences (NAILS), School of life sciences, Nanjing University, 163 Xianlin Road, Nanjing, Jiangsu, 210046, China. This work was supported by grants from the National Natural Science Foundation of China (No.81200201, 81550001, 81250044 and 31301060), the National Basic Research Program of China (973 Program) (No. 2014CB542300), and the Research Special Fund for Public Welfare Industry of Health (No. 201302018).

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