Cardiac natriuretic peptides promote adipose ‘browning’ through mTOR complex-1

Abstract

ObjectiveActivation of thermogenesis in brown adipose tissue (BAT) and the ability to increase uncoupling protein 1 (UCP1) levels and mitochondrial biogenesis in white fat (termed ‘browning’), has great therapeutic potential to treat obesity and its comorbidities because of the net increase in energy expenditure. β-adrenergic-cAMP-PKA signaling has long been known to regulate these processes. Recently PKA-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) was shown to be necessary for adipose ‘browning’ as well as proper development of the interscapular BAT. In addition to cAMP-PKA signaling pathways, cGMP-PKG signaling also promotes this browning process; however, it is unclear whether or not mTORC1 is also necessary for cGMP-PKG induced browning.MethodActivation of mTORC1 by natriuretic peptides (NP), which bind to and activate the membrane-bound guanylyl cyclase, NP receptor A (NPRA), was assessed in mouse and human adipocytes in vitro and mouse adipose tissue in vivo.ResultsActivation of mTORC1 by NP-cGMP signaling was observed in both mouse and human adipocytes. We show that NP-NPRA-PKG signaling activate mTORC1 by direct PKG phosphorylation of Raptor at Serine 791. Administration of B-type natriuretic peptide (BNP) to mice induced Ucp1 expression in inguinal adipose tissue in vivo, which was completely blocked by the mTORC1 inhibitor rapamycin.ConclusionOur results demonstrate that NP-cGMP signaling activates mTORC1 via PKG, which is a component in the mechanism of adipose browning.

Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat

“…A study of mice fed a chow diet containing 42 p.p.m. encapsulated rapamycin for 2 weeks exhibited reduced thermogenic gene expression and worsened glucose tolerance (Tran et al, 2016), whereas studies by Liu and colleagues likewise observed decreased Ucp1 expression with 4-5 mg kg −1 rapamycin treatment (Liu et al, 2016;Liu, Ceddia, & Collins, 2018). Notably, these studies used acute rapamycin treatment at a dose that was two to three times higher than in the present study, suggesting important effects of the dose and duration of treatment with rapamycin that require additional study.…”

“…While the increase in white adipose tissue Ucp1 expression observed herein has previously been suggested in mice deficient in adipocyte mTOR (Shan et al , 2016), several recent studies suggest the opposite. A study of mice fed a chow diet containing 42 ppm encapsulated rapamycin for two weeks exhibited reduced thermogenic gene expression and worsened glucose tolerance (Tran et al , 2016), while studies by Liu et al similarly observed decreased Ucp1 expression with 4–5 mg/kg rapamycin treatment (Liu et al , 2016; Liu et al , 2018). Notably, these studies used acute rapamycin treatment at a dose that was 2–3 times higher than in the current study, suggesting important dose and treatment duration effects of rapamycin that require additional study.…”

Natriuretic Peptides in Cardiovascular and Metabolic Crosstalk

“…47 The response requires mTORC1 (mammalian target of rapamycin complex 1) activation through direct Raptor Ser791 phosphorylation. 48 Natriuretic peptide signaling in adipocytes increases both oxygen consumption rate and mitochondrial oxidative gene expression. The process may involve AMP-activated protein kinase.…”

Adipose tissue browning in mice and humans

“…However, this study does not allow to draw any conclusions about the effect of sildenafil on classical human BAT because only three participants underwent 18 F-FDG PET/CT scans (Li et al 2018). Interestingly, previous preclinical work had already suggested that cGMP and consecutive mTOR activation are also mechanistically involved in the induction of a thermogenic gene program (Liu et al 2018).…”