Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy

Abstract

Aging of white adipose tissue (WAT) is associated with reduced insulin sensitivity, which contributes to whole-body glucose intolerance. WAT aging in mice impairs cold-induced beige adipocyte recruitment (beiging), which has been attributed to the senescence of adipose progenitor cells. Tumor suppressor p53 has also been implicated in WAT aging. However, whether p53-related cellular aging in mature white adipocytes is causative of age-impaired WAT beiging remains unknown. It is also unclear whether transient p53 inhibition can rescue WAT beiging. Herein, we report that p53 increased in adipose tissues of 28-wk-old (aged) mice with impaired beiging capability. Cold exposure decreased p53 in beiging WAT of young mice but not in aged mice. In aged mice, inducible p53 ablation in differentiated adipocytes restored cold-induced WAT beiging and augmented whole-body energy expenditure and insulin sensitivity. Transient pharmacological inhibition of p53 led to the same beneficial effects. Mechanistically, cold exposure repressed autophagy in beiging WAT of young mice yet increased autophagy in aged WAT. p53-ablation reduced microtubule-associated protein light chain 3-mediated mitochondria clearance (mitophagy) and hence facilitated the increase of mitochondria during beiging. These findings suggest that p53-induced mitophagy in aged white adipocytes impedes WAT beiging and may be therapeutically targeted to improve insulin sensitivity in aged WAT.-Fu, W., Liu, Y., Sun, C., Yin, H. Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy.

p53 Functions in Adipose Tissue Metabolism and Homeostasis

“…The observed metabolic changes cannot directly be attributed to adipose tissue and rather represent a cumulative effect of p53 deficiency in other cells and tissues such as hypothalamic centers that regulate feeding behavior [ 137 ]. Only a few studies manipulated p53 directly in adipose tissue [ 122 ] or employed adipose tissue specific knockout mice [ 67 , 68 , 71 , 125 ]. In the latter case, most studies used a system in which p53 ablation was driven by the Fabp4 promoter (Fabp4-Cre mice crossed with p53 floxed mice).…”

“…More specific mouse models are available by now, like systems based on the BAT-specific Ucp1 promoter [ 127 ] or WAT-specific resistin ( Retn ) or Adipoq promoters [ 137 , 138 ]. Furthermore, tamoxifen-responsive inducible Cre systems have been developed that could help to investigate more acute and development-independent functions of p53 in adipose tissues [ 140 , 141 ], as shown in a recent study [ 125 ]. Thirdly, it would be essential to gain insight into the adipose tissue-specific p53 cistrome and the set of target genes regulated if certain stresses are prevalent (e.g., high levels of free FAs).…”

“…In one, higher expression levels of genes involved in β-oxidation and of Ucp1 protein were observed in inguinal WAT of p53 knockout mice [ 54 ]. The other report employed the WAT-specific and inducible Adipoq-creER/p53flox system to show that the age-dependent decline in cold-induced browning of inguinal WAT can be rescued by transient ablation of p53 , which was concomitant with a reduction in mitophagy [ 125 ]. However, more work is needed to delineate how manipulation of p53 or its signaling could impact WAT browning.…”

Emerging Roles for the INK4a/ARF (CDKN2A) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes

“…Whether p16INK4a and p19ARF pathways modulate AT plasticity through transdifferentiation of fully differentiated adipocytes remains elusive. However, inducible ablation or pharmacological inhibition of p53 in mature adipocytes of mice restore cold-induced beiging and increase energy expenditure and insulin sensitivity [ 79 ].…”

Senescent cells in the development of cardiometabolic disease

“…Similarly, adipocyte-specific deletion of p53 or inhibition of p53 using pifithrin-α resulted in enhanced beige adipocyte formation upon cold exposure, increased energy expenditure and improved glucose clearance. Mechanistically, increased expression of p53 in aged adipose tissue appears to prevent adipocyte beiging through stimulation of mitophagy and prevention of increase in mitochondrial mass necessary for white-to-beige adipocyte conversion [51]. AP20187 treatment of naturally aged mice carrying the INK-ATTAC transgene, which allows for selective elimination of p16 Ink4a -positive cells upon administration of AP20187 (Table 1), resulted in reduced circulating levels of activin A, enhanced expression of adipogenic transcription factors and reduced fat loss, although it should be noted that clearance of senescent cells was not demonstrated [32].…”