p38α blocks brown adipose tissue thermogenesis through p38δ inhibition

Abstract

Adipose tissue has emerged as an important regulator of whole-body metabolism, and its capacity to dissipate energy in the form of heat has acquired a special relevance in recent years as potential treatment for obesity. In this context, the p38MAPK pathway has arisen as a key player in the thermogenic program because it is required for the activation of brown adipose tissue (BAT) thermogenesis and participates also in the transformation of white adipose tissue (WAT) into BAT-like depot called beige/brite tissue. Here, using mice that are deficient in p38α specifically in adipose tissue (p38αFab-KO), we unexpectedly found that lack of p38α protected against high-fat diet (HFD)-induced obesity. We also showed that p38αFab-KO mice presented higher energy expenditure due to increased BAT thermogenesis. Mechanistically, we found that lack of p38α resulted in the activation of the related protein kinase family member p38δ. Our results showed that p38δ is activated in BAT by cold exposure, and lack of this kinase specifically in adipose tissue (p38δ Fab-KO) resulted in overweight together with reduced energy expenditure and lower body and skin surface temperature in the BAT region. These observations indicate that p38α probably blocks BAT thermogenesis through p38δ inhibition. Consistent with the results obtained in animals, p38α was reduced in visceral and subcutaneous adipose tissue of subjects with obesity and was inversely correlated with body mass index (BMI). Altogether, we have elucidated a mechanism implicated in physiological BAT activation that has potential clinical implications for the treatment of obesity and related diseases such as diabetes.

Blockade of p38 kinase impedes the mobilization of protumorigenic myeloid populations to impact breast cancer metastasis

“…Notably, inhibition of p38-α may trigger activation of p38-δ, indicating a more complex interdependence of the kinase isoforms. 59 Thus, while our study suggests a link of p38-α/β isoforms to tumor-induced myeloid cell mobilization, these and other reported findings reinforce the complexity of the p38-mediated networks in tumor progression and metastasis.…”

Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

“…Mechanistically, inhibition of p38α stimulates the UCP1 transcription through PKA and its downstream target CREB [176]. However, these observations are in contradiction with a recently published study using the same in vivo model, and showing that adipocyte-specific p38α knockout mice were protected against HFD-induced obesity, had increased energy expenditure and a higher BAT thermogenesis [177]. Lack of p38α in BAT resulted in higher activation of p38δ, suggesting that p38α controls p38δ activity, thereby regulating thermogenesis and energy homeostasis.…”

“…Experiments with p38 inhibitors and p38α knockout cells have shown that p38 phosphorylates and activates C/EBPβ, leading to adipogenesis via PPARγ upregulation [181]. However, lack of p38α in preadipocytes did not affect their differentiation to adipocytes, nor did it affect changes in the differentiation markers evaluated in the major fat depots [177].…”

“…in browning and thermogenesis [173,176,177]. Similar to adipocytes, p38 isoforms present various functions in pancreatic β-cells and skeletal muscle [186][187][188][189]207,208].…”

“…Lack of p38α in BAT resulted in higher activation of p38δ, suggesting that p38α controls p38δ activity, thereby regulating thermogenesis and energy homeostasis. In contrast, in WAT, p38α would have opposite effects depending on the fat depots, blocking browning through inhibition of p38γ in inguinal fat (iWAT) [ 177 ], and promoting browning in epididymal fat (eWAT) [ 173 ]. Moreover, β3-adrenergic-induced p38 and JNK pathways promote hormone-sensitive lipase (HSL)-mediated lipolysis.…”