An AMPK-dependent, non-canonical p53 pathway plays a key role in adipocyte metabolic reprogramming.

Hong Wang,Paul F Pilch,Susan K Fried,Xueping Wan,Libin Liu,Leif W Ellisen

doi:10.7554/elife.63665

Abstract

It has been known adipocytes increase p53 expression and activity in obesity, however, only canonical p53 functions (i.e. senescence and apoptosis) are attributed to inflammation-associated metabolic phenotypes. Whether or not p53 is directly involved in mature adipocyte metabolic regulation remains unclear. Here we show p53 protein expression can be up-regulated in adipocytes by nutrient starvation without activating cell senescence, apoptosis, or a death-related p53 canonical pathway. Inducing the loss of p53 in mature adipocytes significantly reprograms energy metabolism and this effect is primarily mediated through a AMP-activated protein kinase (AMPK) pathway and a novel downstream transcriptional target, lysosomal acid lipase (LAL). The pathophysiological relevance is further demonstrated in a conditional and adipocyte-specific p53 knockout mouse model. Overall, these data support a non-canonical p53 function in the regulation of adipocyte energy homeostasis and indicate that the dysregulation of this pathway may be involved in developing metabolic dysfunction in obesity.

Highlights

White adipose tissue (WAT) plays a central role in nutrient homeostasis, serving as the site of calorie storage and the source of key adipokines (Guilherme et al, 2008; Rosen and Spiegelman, 2006; Kahn et al, 2019)
We demonstrated that p53 plays a critical role in reprogramming adipocyte glucose and lipid metabolisms and that the down-regulation of p53 increases glycolysis capacity and inhibits lipolysis activity simultaneously, which may result in Warburg-like metabolic effects in adipocytes and contribute to increased adipocyte metabolic flexibility and insulin sensitivity in obesity
Lactate tolerance test (L) and in-vivo glucose uptake assay (M) were performed in WT and KO mice. (N) The histology H-E staining was conducted in epididymal fat tissues from WT and p53-KO mice under feeding and fasting (Fasted, 24 hr) conditions. (O–P) Respiratory exchange ratio (RER) was measured in metabolic cage studies. (Q) Total and phosphor-p53, AMPK, and tubulin expression levels in fed and fasted p53-knockout (KO) and wild-type (WT) mice were examined by western blots. (R) Study design of high-fat diet feeding studies

Summary

Introduction

White adipose tissue (WAT) plays a central role in nutrient homeostasis, serving as the site of calorie storage and the source of key adipokines (Guilherme et al, 2008; Rosen and Spiegelman, 2006; Kahn et al, 2019). (iv) Lastly, a lack of attention to adipocyte differentiation affected by p53: p53 is known to regulate adipocyte differentiation and fat tissue development in various ways (Thompson et al, 1998; Inoue et al, 2008; Okita et al, 2014) that may significantly impact energy metabolism when common germline or embryonic p53 knockout mouse models are used Due to these limitations, further studies into the physiological role of p53 in adipocyte metabolism are needed. We created inducible in vitro and in-vivo working models, in which adipocyte-specific p53 expression levels could be manipulated at precisely controlled time points, so that p53 could be expressed normally during adipocyte differentiation and tissue development The results from these working systems demonstrated a central role played by p53 in adipocyte energy metabolic reprogramming under challenging metabolic conditions. This non-canonical p53 function explains the metabolic effect of metformin in adipocytes and has the potential to generate new pharmaceutical approaches for modulating the p53 pathway and, directly improving adipocyte functionality

Results

Discussion

Materials and methods