A MetAP2 inhibitor blocks adipogenesis, yet improves glucose uptake in cells

Abstract

Adipose tissue expansion involves angiogenesis to remodel its capillary network. The enzymemethionine aminopeptidase 2(MetAP2) promotes angiogenesis.MetAP2 inhibitors suppress angiogenesis and have potential anti-obesity effect. However, impairment in adipose tissue expansion is also linked with impaired glycemic control.This study investigated the effect of BL6, a MetAP2 inhibitor, on adipogenesis and glucose disposal.To test effect on angiogenesis, Human Umbilical Vein Endothelial Cells(HUVECs) were treated with BL6 for 24h to determine tube formation. Further, to test effect on adipogenesis and glucose disposal,3T3-L1 pre-adipocytes were treated with BL6(0 µM, 20µM, 50 µM or 100µM) during differentiation. Differentiated cells were stained with Oil Red O for determining lipid accumulation, and glucose uptake assay. Protein levels and RNA expression for key genes involved in the adipogenic cascade were determined.BL6 treatment of HUVECs dose dependently blocked angiogenesis. During differentiation of pre-adipocytes, 50μM and 100µM BL6 significantly reduced lipid accumulation. Treatment with 100µM BL6 significantly decreased expression of adipogenic genes. Interestingly, BL6 treatment dose dependently increased glucose uptake by 3T3-L1 cells.MetAP2 inhibitor blocks angiogenesis, attenuates adipogenesis, yet increases cellular glucose uptake. Collectively this proof of concept study supports a possible role for MetAP2 inhibitor BL6, as a putative anti-obesity therapeutic agent.

Trends in Antidiabetic Drug Discovery: FDA Approved Drugs, New Drugs in Clinical Trials and Global Sales

“…However, recent studies have shown that inhibition of MetAP2 is a strong candidate for treating obesity and diabetes ( Joharapurkar et al, 2014 ). Inhibition of MetAP2 induced clinically meaningful reductions in blood glucose and increased weight loss ( Siddik et al, 2019 ; Wentworth et al, 2020 ). The clinical agent ZGN-1061 is a MetAP2 inhibitor with promising results with improved glucose control and lowered weight in preclinical studies and a recently completed phase II clinical trial ( Burkey et al, 2018 ; Wentworth et al, 2020 ).…”

MetAP2 inhibition reduces food intake and body weight in a ciliopathy mouse model of obesity

“…In one study, addition of fumagillin to an in vitro pre-adipocyte differentiation assay promoted adipogenesis, but had minimal effects in an in vivo adipogenesis assay 31 . In contrast in another study, addition of a fumagillin derivative to an in vitro pre-adipocyte differentiation study inhibited adipogenesis, yet fumagillin treatment of cells caused enhanced glucose uptake, suggesting metabolically healthier cells 32 . Alternatively, fumagillin has anti-angiogenic effects and a prevailing hypothesis is that changes in angiogenesis induced by fumagillin reduce adipose tissue mass.…”

MetAP2 inhibition reduces food intake and body weight in a ciliopathy mouse model of obesity

“…In one study, addition of fumagillin to an in vitro preadipocyte differentiation assay promoted adipogenesis but had minimal effects in an in vivo adipogenesis assay (30). In contrast, another study showed that a fumagillin derivative inhibited adipogenesis in an in vitro preadipocyte differentiation study, but fumagillin treatment of cells enhanced glucose uptake, indicative of metabolically healthier cells (31). Alternatively, a prevailing hypothesis is that the antiangiogenic effects of fumagillin reduce adipose tissue mass, yet angiogenesis changes did not drive reduction of adipose tissue mass in mice (10).…”