Abstract
Maintenance of energy balance between intake and expenditure is a prerequisite of human health, disrupted in severe metabolic diseases, such as obesity and type 2 diabetes (T2D), mainly due to accumulation of white adipose tissue (WAT). WAT undergoes a morphological and energetic remodelling toward brown adipose tissue (BAT) and the BAT activation has anti-obesity potential. The mechanisms or the regulatory factors able to activate BAT thermogenesis have been only partially deciphered. Identifying novel regulators of BAT induction is a question of great importance for fighting obesity and T2D. Here, we evaluated the role of Hif3α in murine pre-adipocyte 3T3-L1 cell line, a versatile and well characterized biological model of adipogenesis, by gain- and loss-of function approaches and in thermogenesis-induced model in vivo. HIF3A is regulated by inflammation, it modulates lypolysis in adipose tissue of obese adults, but its role in energy metabolism has not previously been investigated. We characterized gene and protein expression patterns of adipogenesis and metabolic activity in vitro and mechanistically in vivo. Overexpression of Hif3α in differentiating adipocytes increases white fat cells, whereas silencing of Hif3α promotes “browning” of white cells, activating thermogenesis through upregulation of Ucp1, Elovl3, Prdm16, Dio2 and Ppargc1a genes. Investigating cell metabolism, Seahorse Real-Time Cell Metabolism Analysis showed that silencing of Hif3α resulted in a significant increase of mitochondrial uncoupling with a concomitant increase in acetyl-CoA metabolism and Sirt1 and Sirt3 expression. The causal Hif3α/Ucp1 inverse relation has been validated in Cannabinoid receptor 1 (CB1) knockout, a thermogenesis-induced model in vivo. Our data indicate that Hif3α inhibition triggers “browning” of white adipocytes activating the beneficial thermogenesis rewiring energy metabolism in vitro and in vivo. HIF3A is a novel player that controls the energy metabolism with potential applications in developing therapy to fight metabolic disorders, as obesity, T2D and ultimately cancer.
Highlights
The frequency of metabolic disorders, such as obesity and type 2 diabetes (T2D) rose up over the last 50 years and the generation of novel therapeutic approaches aimed to ameliorate the balance of energy metabolism in adipose tissue is going to be developed (Tsalamandris et al, 2019)
We recently showed that pro-inflammatory cytokines modulate HIF3A expression in an oxygen-independent manner in mesenchymal stem cells (MSCs) [8], we asked whether the cytokine-mediated effects could regulate fat metabolism and differentiation
We investigated the expression levels of specific key regulators of adipogenesis and we found in inguinal white fat (iFAT) of cannabinoid receptor 1 knockout (CB1KO) mice an increase of uncoupling protein 1 (Ucp1), Elovl3, positive regulatory domain containing 16 (Prdm16), Dio2, Ppargc1a and a decrease of peroxisome proliferator-activated receptor gamma (Pparg), C/ebpα, fatty acid synthase (Fasn) mRNAs, compared to wild type cells (WT) (Figure 6F), confirming the role of Hif3a in controlling adipocytes metabolism in vivo
Summary
The frequency of metabolic disorders, such as obesity and type 2 diabetes (T2D) rose up over the last 50 years and the generation of novel therapeutic approaches aimed to ameliorate the balance of energy metabolism in adipose tissue is going to be developed (Tsalamandris et al, 2019). The adipose tissue is a metabolically dynamic organ, classified as white (WAT) and brown (BAT) adipose tissues with distinctive features. WAT cells are larger, spherical with unilocular lipid droplets helpful for lipid storage. BAT cells are smaller with numerous, little lipid droplets, helpful for lypolysis. Obesity is linked to excessive WAT accumulation, chronic low-grade inflammation, energy imbalance and altered metabolism, prompting the development of insulin resistance, dyslipidaemia behind the high body mass index (BMI) (Townsend and Tseng, 2012). BAT cells are linked with low BMI, low fat mass, normal glucose and cholesterol plasma levels. WAT cells can adopt a thermogenic phenotype in response to environmental stimuli and dietary lifestyle, representing a promising strategy to counteract the metabolic disorders. The causal factors that promote the BAT emergence have been only partially deciphered
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
