Sirtuin 6 supra‐physiological overexpression in hypothalamic pro‐opiomelanocortin neurons promotes obesity via the hypothalamus‐adipose axis

Abstract

Sirtuin 6 (Sirt6), a member of the Sirtuin family, has important roles in maintaining glucose and lipid metabolism. Our previous studies demonstrated that the deletion of Sirt6 in pro‐opiomelanocortin (POMC)‐expressing cells by the loxP‐Cre system resulted in severe obesity and hepatic steatosis. However, whether overexpression of Sirt6 in hypothalamic POMC neurons could ameliorate diet‐induced obesity is still unknown. Thus, we generated mice specifically overexpressing Sirt6 in hypothalamic POMC neurons (PSOE) by stereotaxic injection of Cre‐dependent adeno‐associated viruses into the arcuate nucleus of Pomc‐Cre mice. PSOE mice showed increased adiposity and decreased energy expenditure. Furthermore, thermogenesis of BAT and lipolysis of WAT were both impaired, caused by reduced sympathetic nerve innervation and activity in adipose tissues. Mechanistically, Sirt6 overexpression decreasing STAT3 acetylation, thus lowering POMC expression in the hypothalamus underlined the observed phenotypes in PSOE mice. These results demonstrate that Sirt6 overexpression specifically in the hypothalamic POMC neurons exacerbates diet‐induced obesity and metabolic disorders via the hypothalamus‐adipose axis.

The sirtuin family in health and disease

“…867 SIRT6 overexpression was found to exacerbate diet-induced obesity by decreasing STAT3 acetylation and lowering proopiomelanocortin expression in the hypothalamus. 868 Overall, these findings suggest that high expression of SIRT1 and SIRT3 and low expression of SIRT2 and SIRT6 produced a metabolic state that inhibited the development of obesity, thereby reducing the occurrence of obesity. Therefore, the strategy of developing SIRT activators/inhibitors has important clinical significance to prevent obesity and control the occurrence and development of obesity and related diseases.…”

“… 867 SIRT6 overexpression was found to exacerbate diet-induced obesity by decreasing STAT3 acetylation and lowering pro-opiomelanocortin expression in the hypothalamus. 868 …”

SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases

“…In pro-opiomelanocortin (POMC)-expressing neurons, SIRT6 ensured activation of the leptin-induced JAK-STAT3 signaling cascade, increasing POMC production and thus promoting sympathetic nervous system (SNS) activity, which was closely related to the lipolytic activity and browning of adipose tissue [ 141 ]. Unexpectedly, SIRT6 overexpression has been shown to reduce STAT3 acetylation, which reduced POMC production, impairing SNS activity in adipose tissue [ 142 ]. These findings indicate the importance of maintaining SIRT6 activity within a physiological range.…”

“…Among known activators, pansirtuin activators may not be suitable for human use, as SIRT4 may exert detrimental effects in people with CVDs, such as aggravation of pathological cardiac hypertrophy [ 240 ]. Additionally, other phenomena need to be further studied: depletion and supraphysiological expression of SIRT6 in POMC neurons that disrupt both POMC production and POMC-related metabolism [ 141 , 142 ], and overexpression of SIRT6 that aggravates the instability of atherosclerotic plaques [ 9 , 72 ]. In addition, activators of SIRT6 have been described as potential tools for treating certain cancers; however, SIRT6 acts as a tumor promoter in some cancer types [ 241 ].…”

Effects of the POMC System on Glucose Homeostasis and Potential Therapeutic Targets for Obesity and Diabetes

“… 57 Additionally, Sirt6, a member of the Sirtuin family, has a vital role in maintaining glucose metabolism. 58 The overexpression of Sirt6 can reverse HFD-induced obesity in mice. Conversely, the loss of Sirt6 can affect leptin activity in the POMC neurons, which impairs glucose homeostasis.…”