Abstract
p38 has long been known as a central mediator of protein kinase A (PKA) signaling in brown adipocytes, which positively regulate the transcription of uncoupling protein 1 (UCP-1). However, the physiological role of p38 in adipose tissues, especially the white adipose tissue (WAT), is largely unknown. Here, we show that mice lacking p38α in adipose tissues display a lean phenotype, improved metabolism, and resistance to diet-induced obesity. Surprisingly, ablation of p38α causes minimal effects on brown adipose tissue (BAT) in adult mice, as evident from undetectable changes in UCP-1 expression, mitochondrial function, body temperature (BT), and energy expenditure. In contrast, genetic ablation of p38α in adipose tissues not only markedly facilitates the browning in WAT upon cold stress but also prevents diet-induced obesity. Consistently, pharmaceutical inhibition of p38α remarkably enhances the browning of WAT and has metabolic benefits. Furthermore, our data suggest that p38α deficiency promotes white-to-beige adipocyte reprogramming in a cell-autonomous manner. Mechanistically, inhibition of p38α stimulates the UCP-1 transcription through PKA and its downstream cAMP-response element binding protein (CREB), which form a positive feedback loop that functions to reinforce the white-to-beige phenotypic switch during cold exposure. Together, our study reveals that inhibition of p38α is able to promote WAT browning and confer metabolic benefits. Our study also indicates that p38α in WAT represents an exciting pharmacological target to combat obesity and metabolic diseases.
Highlights
White adipose tissue (WAT) and brown adipose tissue (BAT) are two major types of adipose tissues, which play different physiological roles in whole-body energy homeostasis [1,2]
The functional brown adipose tissue (BAT) identified in human adults consists of classic brown adipocytes and brown-like adipocytes, both of which are important for energy homeostasis
We propose that inhibiting p38α in white adipose tissue (WAT), possibly combined with cold exposure, could constitute an exciting pharmacological target to combat obesity and metabolic diseases
Summary
White adipose tissue (WAT) and brown adipose tissue (BAT) are two major types of adipose tissues, which play different physiological roles in whole-body energy homeostasis [1,2]. The BAT identified in human adults might consist of classic brown adipocytes and brown-like adipocytes (beige adipocytes). It has been indicated that the beige adipocytes interspersed among white adipocytes in rodents are able to alleviate cold stress to restore thermal homeostasis [8]. Promoting the development and formation of beige adipocytes in WAT, called the browning of WAT, increases energy expenditure, prevents diet-induced obesity, and improves glucose metabolism in rodents [9,10], while suppressing WAT browning leads to obesity and insulin resistance [11,12]. Given that beige and brown adipocytes have many distinguishing characteristics [14], it is probable that the regulation of the thermogenic program differs in beige and brown adipocytes, which has yet to be studied
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