Novel GLP-1 Analog Supaglutide Reduces HFD-Induced Obesity Associated with Increased Ucp-1 in White Adipose Tissue in Mice

Abstract

GLP-1, an important incretin hormone plays an important role in the regulation of glucose homeostasis. However, the therapeutic use of native GLP-1 is limited due to its short half-life. We recently developed a novel GLP-1 mimetics (supaglutide) by genetically engineering recombinant fusion protein production techniques. We demonstrated that this formulation possessed long-lasting GLP-1 actions and was effective in glycemic control in both type 1 and type 2 diabetes rodent models. Here, we investigated the effects of supaglutide in regulating energy homeostasis in obese mice. Mice were fed with high-fat diet (HFD) for 6 months to induce obesity and then subjected to supaglutide treatment (300 μg/kg, bi-weekly for 4 weeks), and placebo as control. Metabolic conditions were monitored and energy expenditure was assessed by indirect calorimetry (CLAMS). Cold tolerance test was performed to evaluate brown-adipose tissue (BAT) activities in response to cold challenge. Glucose tolerance and insulin resistance were evaluated by intraperitoneal glucose tolerance test and insulin tolerance tests. Liver and adipose tissues were collected for histology analysis. Expression of uncoupling protein 1(Ucp1) in adipose tissues was evaluated by Western blotting. We found that supaglutide treatment reduced body weight, which was associated with reduced food intake. Compared to the placebo control, supaglutide treatment improved lipid profile, i.e., significantly decreased circulating total cholesterol levels, declined serum triglyceride, and free fatty acid levels. Importantly, the intervention significantly reduced fatty liver, decreased liver triglyceride content, and concomitantly ameliorated liver injury exemplified by declined hepatic alanine aminotransferase (ALT) and aspartic transaminase (AST) content. Remarkably, supaglutide reduced hepatic lipid accumulation and altered morphometry in favor of small adipocytes in fat. This is consistent with the observation that supaglutide increased tolerance of the mice to cold environment associated with up-regulation of Ucp1 in the inguinal fat. Furthermore, supaglutide improved glucose tolerance, and insulin sensitivity in the obese mice suggesting improved glucose and energy homeostasis. Our findings suggest that supaglutide exerts beneficial effect on established obesity through reducing energy intake and is associated with brown remodeling of white adipose tissue.

The key role of a glucagon-like peptide-1 receptor agonist in body fat redistribution

“…It is important to note that liraglutide treatment elicited a general shift to smaller adipocyte sizes in all white adipose depots, which was consistent with the results of a previous report (Wan et al 2017). The size of adipocytes can, to a certain extent, reflect the metabolic function of adipocytes (Wan et al 2017).…”

“…It is important to note that liraglutide treatment elicited a general shift to smaller adipocyte sizes in all white adipose depots, which was consistent with the results of a previous report (Wan et al 2017). The size of adipocytes can, to a certain extent, reflect the metabolic function of adipocytes (Wan et al 2017). Although there is controversy about the harmful range of adipocyte sizes (Verhoef et al 2013), it is generally accepted that the conversion of small adipocytes to large ones is closely related to metabolic diseases.…”

“…Although there is controversy about the harmful range of adipocyte sizes (Verhoef et al 2013), it is generally accepted that the conversion of small adipocytes to large ones is closely related to metabolic diseases. In addition, an increase in the number of small adipocytes can promote lipid metabolism and insulin sensitivity (Wan et al 2017). Our study revealed that adipocyte sizes were reduced after intervention, partly explaining the anti-obesity effects of liraglutide.…”

“…Central administration of GLP-1RAs decreases fatty acid accumulation in WAT, stimulates PGC1α/UCP1related thermogenesis in BAT and increases the uptake of plasma triacylglycerol-derived fatty acids by BAT and WAT actions mediated by inhibition of hypothalamic AMPK phosphorylation and increases in sympathetic outflow (Lockie et al 2012, Kooijman et al 2015, Lopez et al 2015. However, intraperitoneal injection of a GLP-1RA was found to upregulate the expression of Ucp1 in subcutaneous WAT but did not significantly change the expression of Ucp1 in BAT and visceral WAT (Wan et al 2017). Our study showed a similar trend with the latter, although liraglutide was subcutaneously administered.…”

“…Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by gastrointestinal L cells in response to oral nutrient ingestion (Wan et al 2017) and is an ideal therapy for obesity and T2DM (Rajeev & Wilding 2016). However, native GLP-1 has a short circulating half-life (t1/2 < 2 min) that results mainly from rapid enzymatic inactivation by dipeptidyl peptidase-IV (DPP-IV) and/or from rapid kidney clearance (Wan et al 2017). To prolong the action of GLP-1, DPP-IV inhibitors and GLP-1 receptor agonists (GLP-1RAs) are introduced.…”