Mice lacking ANGPTL8 (Betatrophin) manifest disrupted triglyceride metabolism without impaired glucose homeostasis

Abstract

Angiopoietin-like protein (ANGPTL)8 (alternatively called TD26, RIFL, Lipasin, and Betatrophin) is a newly recognized ANGPTL family member that has been implicated in both triglyceride (TG) and glucose metabolism. Hepatic overexpression of ANGPTL8 causes hypertriglyceridemia and increased insulin secretion. Here we examined the effects of inactivating Angptl8 on TG and glucose metabolism in mice. Angptl8 knockout (Angptl8 −/− ) mice gained weight more slowly than wild-type littermates due to a selective reduction in adipose tissue accretion. Plasma levels of TGs of the Angptl8 −/− mice were similar to wild-type animals in the fasted state but paradoxically decreased after refeeding. The lower TG levels were associated with both a reduction in very low density lipoprotein secretion and an increase in lipoprotein lipase (LPL) activity. Despite the increase in LPL activity, the uptake of very low density lipoprotein-TG is markedly reduced in adipose tissue but preserved in hearts of fed Angptl8 −/− mice. Taken together, these data indicate that ANGPTL8 plays a key role in the metabolic transition between fasting and refeeding; it is required to direct fatty acids to adipose tissue for storage in the fed state. Finally, glucose and insulin tolerance testing revealed no alterations in glucose homeostasis in mice fed either a chow or high fat diet. Thus, although absence of ANGPTL8 profoundly disrupts TG metabolism, we found no evidence that it is required for maintenance of glucose homeostasis.

Increased Circulating Levels of Betatrophin in Newly Diagnosed Type 2 Diabetic Patients

“…Mice lacking betatrophin had a 70% reduction in plasma triglyceride levels compared with littermate control subjects (23). Adenovirus-mediated hepatic overexpression of betatrophin increased plasma triglyceride levels more than five-fold (24).…”

Circulating betatrophin is elevated in patients with type 1 and type 2 diabetes

“…Fenzl et al showed that betatrophin was associated with plasma atherogenic lipids in obesity and type 2 diabetes, and not associated with beta cell function and glucose homeostasis [9]. In Angptl8 (betatrophin) knockout mice, serum TG was reduced after refeeding and low TG was associated with reduced very low density lipoprotein secretion and increased LPL activity, but not with glucose impairment in glucose tolerance tests [18]. Betatrophin (Angptl8) inhibits LPL activity directly or indirectly by promoting Angptl3 cleavage, since cleavage of Angptl3 inhibits LPL activity directly [19][20][21][22].…”

Angiopoietin-like 8 (Angptl8) controls adipocyte lipolysis and phospholipid composition

“…Under circumstances favouring FA deposition as TGs in WAT, it is plausible that hydrolysis of the stored TGs should simultaneously be suppressed. It thus seems that, analogous to the activity of Angptl8 as an inhibitor of lipolysis in the circulation (Quagliarini et al, 2012;Wang et al, 2013), it could execute a similar function intracellularly. We failed to detect changes in the mRNA expression of central mediators of lipolysis, ATGL and HSL, while a small increase of the Angptl4 message was evident; Angptl4 acts as stimulator of adipocyte lipolysis (Gray et al, 2012), so its induction could contribute to the observed increase of lipolysis.…”

“…Since we saw in the Angptl8 KD adipocytes a reduction of stored TGs and because Angptl8 together with Angptl3 inhibits LPL activity in the circulation (Quagliarini et al, 2012;Wang et al, 2013), we decided to measure the intracellular lipolysis in the Angptl8 and control adipocytes in the presence or absence of b-adrenergic (isoproterenol) stimulation. Measurement of NEFA released into the culture medium revealed a significant enhancement of lipolysis in both KD1 and KD2 cell pools as compared to the non-targeting control, the volume of the effect being more pronounced for KD1.…”

“…Overexpression of Angptl8 in hepatocytes was reported to enhance insulin signaling via the Akt-GSK3β and Akt-FoxO1 pathways (Rong Guo et al, 2016). Characterization of Angptl8 knockout mice provided evidence for an important role of the protein in the postprandial distribution of FAs between storage in WAT and tissues which oxidize them (Wang et al, 2013). …”