FoxO1 interacts with transcription factor EB and differentially regulates mitochondrial uncoupling proteins via autophagy in adipocytes

Abstract

Mitochondrial uncoupling proteins (UCPs) are inducible and play an important role in metabolic and redox homeostasis. Recent studies have suggested that FoxO1 controls mitochondrial biogenesis and morphology, but it remains largely unknown how FoxO1 may regulate mitochondrial UCPs. Here we show that FoxO1 interacted with transcription factor EB (Tfeb), a key regulator of autophagosome and lysosome, and mediated the expression of UCP1, UCP2 and UCP3 differentially via autophagy in adipocytes. UCP1 was down-regulated but UCP2 and UCP3 were upregulated during adipocyte differentiation, which was associated with increased Tfeb and autophagy activity. However, inhibition of FoxO1 suppressed Tfeb and autophagy, attenuating UCP2 and UCP3 but increasing UCP1 expression. Pharmacological blockade of autophagy recapitulated the effects of FoxO1 inhibition on UCPs. Chromatin immunoprecipitation assay demonstrated that FoxO1 interacted with Tfeb by directly binding to its promoter, and silencing FoxO1 led to drastic decrease in Tfeb transcript and protein levels. These data provide the first line of evidence that FoxO1 interacts with Tfeb to regulate autophagy and UCP expression in adipocytes. Dysregulation of FoxO1→autophagy→UCP pathway may account for metabolic changes in obesity.

The adrenergic-induced ERK3 pathway drives lipolysis and suppresses energy dissipation

“…Moreover, these mice show increased energy expenditure when fed HFD and maintained under room temperature. These results are in line with the fact that FOXO1 promotes Atgl expression but suppresses Ucp1 transcription (Nakae et al 2008(Nakae et al , 2012Chakrabarti and Kandror 2009b;Chakrabarti et al 2011;Liu et al 2016;Kita et al 2019;Peng et al 2019). Therefore, it appears that at least upon HFD feeding, suppression of Ucp1 expression and energy expenditure would play a dominant role over ATGL-dependent lipolysis.…”

“…We and others showed that FOXO1 promotes the expression of Atgl (Chakrabarti and Kandror 2009b;Chakrabarti et al 2011;Jung et al 2019). Interestingly, a number of reports showed that FOXO1 suppresses the expression of genes regulating energy dissipation, including UCP1, in white and brown adipocytes (Nakae et al 2008(Nakae et al , 2012Liu et al 2016;Kita et al 2019;Peng et al 2019). However, a recent study indicated that in brown adipose tissue of mice fed ND, FOXO1 does not affect UCP1 and in vitro under specific culture conditions deletion of FOXO1 might even decrease Ucp1 expression in brown adipocytes (Jung et al 2019).…”

“…Paradoxically, it has been shown that reducing ATGL action can also protect against diabetes (Haemmerle et al 2006;Arner and Langin 2014;Schoiswohl et al 2015;Schreiber et al 2015). In addition to its role regulating Atgl expression, FOXO1 promotes differentiation of adipocytes and suppresses expression of uncoupling protein 1 (UCP1), which drives energy expenditure and therefore counteracts lipid accumulation (Nakae et al 2003(Nakae et al , 2008(Nakae et al , 2012Liu et al 2016;Kita et al 2019;Peng et al 2019).…”

Adipose Tissue and FoxO1: Bridging Physiology and Mechanisms

“…In fact, during white-to-brown conversion stimulated by cold exposure or forskolin treatment (a pharmacological agent that raises intracellular cAMP levels [75]), FoxO1 undergoes inactivation by the co-repressor ZFP238 that, in this way, allows the expression of UCP1 and mitochondrial biogenesis-associated genes [76]. Moreover, FoxO1 activity has been demonstrated to induce autophagy during adipocyte differentiation which has been linked to the downregulation of UCP1 and upregulation of UCP2/3 [77]. This result correlates well with the notion that inhibition of autophagy leads to browning of white adipose tissue, which is manifested by an increased expression of UCP1 [78,79].…”

“…In particular, FoxO1 directly binds to the promoter of the transcription factor EB (TFEB), a key regulator of autophagosome and lysosome biogenesis, promoting its transcription during adipocyte differentiation. The use of the FoxO1 antagonist AS1842856 significantly reduced TFEB expression, and thus the induction of autophagy, with consequences on the coordinated expression of UCP1/2/3 during adipocytes differentiation [65,77].…”