Prolyl Isomerase Pin1 Suppresses Thermogenic Programs in Adipocytes by Promoting Degradation of Transcriptional Co-activator PRDM16

Abstract

Non-shivering thermogenesis in adipocytes provides defense against low temperatures and obesity development, but the underlying regulatory mechanism remains to be fully clarified. Based on both markedly increased Pin1 expression in states of excess nutrition and resistance to obesity development in Pin1 null mice, we speculated that adipocyte Pin1 may play a role in thermogenic programs. Adiposespecific Pin1 knockout (adPin1 KO) mice showed enhanced transcription of thermogenic genes and tolerance to hypothermia when exposed to cold. In addition, adPin1 KO mice were resistant to high-fat diet-induced obesity and glucose intolerance. A series of experiments revealed that Pin1 binds to PRDM16 and thereby promotes its degradation through the ubiquitin-proteasome system. Consistent with these results, Pin1 deletion in differentiated adipocytes showed enhancement of thermogenic programs in response to the b3 agonist CL316243 through the upregulation of PRDM16 proteins. These observations indicate that Pin1 is a negative regulator of non-shivering thermogenesis.

Pin1 Plays Essential Roles in NASH Development by Modulating Multiple Target Proteins

“…Hepatic steatosis results from an imbalance between lipogenesis and fatty acid oxidation [30]. As described above, hepatic Pin1 expressions are increased by either an HFD or MCDD, and hepatic steatosis does not occur in Pin1 knockout (KO) mice [37]. These findings indicate Pin1 in the liver to be essential for the development of steatosis.…”

“…First, insulin signaling plays critical roles in lipogenesis, by inducing the expressions of two rate-limited enzymes, acetyl CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN) [38,39]. Pin1 reportedly enhances insulin signaling via its association with insulin receptor substrate 1 (IRS-1) and Akt [37,40]. Pin1 binds to IRS-1 and upregulates its tyrosine phosphorylation without altering IRS-1 protein levels.…”

“…Pin1 binds to IRS-1 and upregulates its tyrosine phosphorylation without altering IRS-1 protein levels. Indeed, Pin1 null mice were revealed to have impaired insulin sensitivity [37]. Moreover, Pin1 raises the level of Akt phosphorylation at Ser473 through the stabilization of the total Akt protein amount [39].…”

Pinning Down the Transcription: A Role for Peptidyl-Prolyl cis-trans Isomerase Pin1 in Gene Expression

“…A recent study also demonstrates that transcriptional coactivator PRDM16 is negatively regulated by Pin1 (Nakatsu et al, 2019). PRDM16 plays crucial roles in the determination and function of brown and beige fat as well as in hematopoiesis and cardiac development (Chi and Cohen, 2016).…”

“…The significance of these biochemical studies in gene regulation would be strengthened if similar regulatory mechanism would be confirmed in Pin1 −/− or Pin1 conditional knockout mice in combination with mouse disease models. A great example is demonstrated in a recent study of the identification of Pin1 as a regulator of thermogenesis by targeting PRDM16 for degradation (Nakatsu et al, 2019).…”