Antiobesity efficacy of GLP‐1 receptor agonist liraglutide is associated with peripheral tissue‐specific modulation of lipid metabolic regulators

Abstract

To investigate the role of glucagon-like-peptide-1 receptor (GLP-1R) in peripheral lipid metabolism. Both lean and high-fat diet (HFD)-induced obesity (DIO) rats were used to compare the peripheral effects of the subcutaneous and repeated administration of the GLP-1R agonist liraglutide on the expression of key regulators involved in lipid metabolism, β-oxidation and thermogenesis in liver, abdominal muscle, and epididymal white adipose tissue (eWAT). We observed that liraglutide reduced caloric intake, body weight, and plasma levels of triglycerides and VLDL in a diet-independent manner. However, changes in liver fat content and the expression of lipid metabolism regulators were produced in a diet and tissue-dependent manner. In lean rats, liraglutide increased the gene/protein expression of elements involved in lipogenesis (ChREBP, Acaca/ACC, Fasn/FAS, Scd1/SCD1, PPARα/γ), β-oxidation (CPT1b), and thermogenesis (Cox4i1, Ucp1/UCP1) in eWAT and muscle, which suggest an increase in fatty-acid flux and utilization to activate energy expenditure. Regarding DIO rats, the specific reduction of liver lipid content by liraglutide was associated with a decreased expression of main elements involved in lipogenesis (phospho-ACC), peroxisomal β-oxidation (ACOX1), and lipid flux/storage (Pparγ/PPARγ) in liver, which suggest a recovery of lipid homeostasis. Interestingly, the muscle of DIO rats treated with liraglutide showed a decreased expression of PPARγ and the thermogenic factor UCP1. These results help us to better understand the peripheral mechanisms regulating lipid metabolism that underlay the effectiveness of GLP-1 analogues for the treatment of diabetes and obesity. © 2016 BioFactors, 42(6):600-611, 2016.

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

“…In our current study, the mice were subjected to the CLAMS system for analysis of metabolic status at the end of the experiment, but the weight reduction effect was seen after the first drug injection and maintained throughout the experiment, rendering the possibility that we might have missed the best time window to quantify EE that significantly influences body weight gain. Nevertheless, our data that Supaglultide-treated mice demonstrated a concomitantly increased trend of EE both on per-whole-animal and BW-normalized basis suggested that supaglutide exerted a regulatory effect on the energy expenditure of the obese mice, which is in good agreement with previous studies in both preclinical and clinical obese subjects (Kanoski et al, 2011; Fukuda-Tsuru et al, 2014; Shah and Vella, 2014; Decara et al, 2016; Rondanelli et al, 2016; Xu et al, 2016). It is important to note, the tissue-specific modulation of lipid metabolism and WAT remodeling of GLP-1 represents a molecular mechanism in mediating GLP-1's anti-obesity actions (Decara et al, 2016; Xu et al, 2016).…”

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

“…Possible mechanisms involved in the reduction of hepatic fat accumulation after GLP-1RAs intervention include an enhancement of hepatic lipophagy, a reduction in lipid synthesis, VLDL overproduction and lipotoxicity, and a change in hepatocyte enzyme expression levels, which favors a switch in energy utilization from carbohydrate to lipid (Panjwani et al 2013, Taher et al 2014. Induction of autophagy via the AMPK/mTOR pathway (Decara et al 2016) was also reported as one of the possible mechanisms. Other studies demonstrated…”

Cooperative role of the glucagon‐like peptide‐1 receptor and β3‐adrenergic‐mediated signalling on fat mass reduction through the downregulation of PKA/AKT/AMPK signalling in the adipose tissue and muscle of rats

“…Contrary to the effect occurring centrally, GLP‐1 increased cAMP and AMPK phosphorylation in hepatocytes, resulting in the downregulation of lipogenic enzymes and upregulation of lipolytic CPT1 . Recent studies in high‐fat‐fed rodents treated with GLP‐1 analogs indicated that the specific reduction in liver steatosis and very low‐density lipoprotein (VLDL) overproduction was associated with decreased expression of main elements involved in lipogenesis (phospho‐ACC), peroxisomal β‐oxidation (ACOX1) and lipid flux (PPARγ) in the liver, as well as increased expression of lipolytic genes ( Hsl , Vlcad , Acox1 ) in adipose tissue . Interestingly, a recent study indicated that UCP1, a major regulator of non‐shivering thermogenesis, was specifically downregulated in the muscle of obese rats treated with liraglutide and suggests a link between uncoupling proteins and the expression of peroxisome proliferator‐activated receptors .…”

“…Recent studies in high‐fat‐fed rodents treated with GLP‐1 analogs indicated that the specific reduction in liver steatosis and very low‐density lipoprotein (VLDL) overproduction was associated with decreased expression of main elements involved in lipogenesis (phospho‐ACC), peroxisomal β‐oxidation (ACOX1) and lipid flux (PPARγ) in the liver, as well as increased expression of lipolytic genes ( Hsl , Vlcad , Acox1 ) in adipose tissue . Interestingly, a recent study indicated that UCP1, a major regulator of non‐shivering thermogenesis, was specifically downregulated in the muscle of obese rats treated with liraglutide and suggests a link between uncoupling proteins and the expression of peroxisome proliferator‐activated receptors . Fatty acid flux and utilization to activate energy expenditure were particularly striking in non‐obese, non‐diabetic rats because of an increased expression of elements involved in lipogenesis (ACC, FAS, SCD1), fatty acid β‐oxidation (PPARα/γ, CPT1b) and thermogenesis (UCP1) in WAT and muscle .…”