Bif-1 deficiency impairs lipid homeostasis and causes obesity accompanied by insulin resistance

Abstract

Bif-1 is a membrane-curvature inducing protein that is implicated in the regulation of autophagy and tumorigenesis. Here, we report that Bif-1 plays a critical role in regulating lipid catabolism to control the size of lipid droplets and prevent the development of obesity and insulin resistance upon aging or dietary challenge. Our data show that Bif-1 deficiency promotes the expansion of adipose tissue mass without altering food intake or physical activities. While Bif-1 is dispensable for adipose tissue development, its deficiency reduces the basal rate of adipose tissue lipolysis and results in adipocyte hypertrophy upon aging. The importance of Bif-1 in lipid turnover is not limited to adipose tissue since fasting and refeeding-induced lipid droplet clearance is also attenuated by Bif-1 loss in the liver. Interestingly, obesity induced by a high fat-diet or Bif-1 deficiency downregulates the expression of proteins involved in the autophagy-lysosomal pathway, including Atg9a and Lamp1 in the adipose tissue. These findings thus identify Bif-1 as a novel regulator of lipid homeostasis to prevent the pathogenesis of obesity and its associated metabolic complications.

The soluble guanylate cyclase stimulator IW‐1973 prevents inflammation and fibrosis in experimental non‐alcoholic steatohepatitis

“…Autophagy is an evolutionary conserved catabolic process by which cellular components are engulfed in an autophagosome and delivered to the lysosome for degradation (Kaur and Debnath, ). Autophagy is emerging as a potential regulator of lipid metabolism and obesity (Liu et al ., ), because this process mediates the lipolysis of TAG and reduces the storage of lipids in adipocytes (Singh et al ., ; López‐Vicario et al ., ; Soussi et al ., ). Finally, it is important to mention that in contrast to previous reports by Mitschke et al .…”

Breaking fat: The regulation and mechanisms of lipophagy

“…These authors demonstrated that an inhibition of lysosomal function in macrophages not only favored increased lipid retention, but also resulted in reduced levels of lipolysis in the WAT. The membrane curvature-sensing protein endophilin B1, known to be highly expressed in human adipose tissue, may also play a key role in obesity: genetic knockouts of endophilin B1 resulted in mice that displayed an enhanced susceptibility to body weight gain compared to control littermates [113]. In contrast to WAT, lipophagy may play a more important role in lipid homeostasis in the metabolically active brown adipose tissue: indeed, Martinez-Lopez et al .…”

Regulation and Functions of Autophagic Lipolysis

“…A novel protein recently implicated in the regulation of autophagic lipolysis is the membrane curvature protein Bif-1 [28]. In adipocytes, autophagy induces Bif-1-dependent PLIN1 degradation and Bif-1 deficiency leads to decreased TG hydrolysis, suggesting that PLIN1 degradation is necessary for autophagy-driven LD breakdown.…”

“…Bif-1 deficiency resulted in adipose tissue hypertrophy, obesity and hyperinsulinemia with high fat diet feeding or aging. However, Bif-1 deficiency did not inhibit adipose tissue lipolysis upon fasting [28], suggesting that lipophagy is not essential to hormone-stimulated adipocyte lipolysis. Cell-type differences may therefore exist in lipophagy, but interpretation of the role of lipophagy in adipose tissue is complicated by effects of autophagy on adipocyte differentiation [29,30], although loss of Bif-1 was reported not to have this effect [28].…”

“…However, Bif-1 deficiency did not inhibit adipose tissue lipolysis upon fasting [28], suggesting that lipophagy is not essential to hormone-stimulated adipocyte lipolysis. Cell-type differences may therefore exist in lipophagy, but interpretation of the role of lipophagy in adipose tissue is complicated by effects of autophagy on adipocyte differentiation [29,30], although loss of Bif-1 was reported not to have this effect [28]. Decreased levels of the autophagy related proteins Atg9a and Lamp1 in Bif-1 knockout mice upon dietary challenge or aging suggest that defective autophagy might contribute to the LD accumulation in these mice.…”