GLP-1(32-36)amide Pentapeptide Increases Basal Energy Expenditure and Inhibits Weight Gain in Obese Mice

Abstract

The prevalence of obesity-related diabetes is increasing worldwide. Here we report the identification of a pentapeptide, GLP-1(32-36)amide (LVKGRamide), derived from the glucoincretin hormone GLP-1, that increases basal energy expenditure and curtails the development of obesity, insulin resistance, diabetes, and hepatic steatosis in diet-induced obese mice. The pentapeptide inhibited weight gain, reduced fat mass without change in energy intake, and increased basal energy expenditure independent of physical activity. Analyses of tissues from peptide-treated mice reveal increased expression of UCP-1 and UCP-3 in brown adipose tissue and increased UCP-3 and inhibition of acetyl-CoA carboxylase in skeletal muscle, findings consistent with increased fatty acid oxidation and thermogenesis. In palmitate-treated C2C12 skeletal myotubes, GLP-1(32-36)amide activated AMPK and inhibited acetyl-CoA carboxylase, suggesting activation of fat metabolism in response to energy depletion. By mass spectroscopy, the pentapeptide is rapidly formed from GLP-1(9-36)amide, the major form of GLP-1 in the circulation of mice. These findings suggest that the reported insulin-like actions of GLP-1 receptor agonists that occur independently of the GLP-1 receptor might be mediated by the pentapeptide, and the previously reported nonapeptide (FIAWLVKGRamide). We propose that by increasing basal energy expenditure, GLP-1(32-36)amide might be a useful treatment for human obesity and associated metabolic disorders.

‘Browning’ the cardiac and peri-vascular adipose tissues to modulate cardiovascular risk

“…When delivered through intracerebroventricular injection, GLP-1 [114] and its analogue exendin-4 [115] increase BAT thermogenesis, mediated via an increased uptake of TG-derived FA's and plasma glucose in addition to browning WAT, effects which may occur by activation of hypothalamic AMPK [116]. Similar results have been demonstrated when GLP-1 agonists have been administered peripherally [117], [118], [119] with the browning of WAT suggested to occur via upregulation of SIRT1 [120]. Whilst these effects remain to be confirmed in humans it is feasible that GLP-1 agonists could be suitable candidates to induce browning of visceral adipose tissues.…”

PGLP‐1, a novel long‐acting dual‐function GLP‐1 analog, ameliorates streptozotocin‐induced hyperglycemia and inhibits body weight loss

“…GLP‐1 can also increase β‐cell mass by stimulating β‐cell proliferation and inhibiting apoptosis (4, 5). Moreover, GLP‐1(9‐36)amide was defined as a product of GLP‐1 (7‐36)amide degradation by the dipeptidyl peptidase IV (DPP‐IV). Because of its weak insulin‐tropic activities, it was often referred to as the inactive metabolite of GLP‐1.…”

“…Because of its weak insulin‐tropic activities, it was often referred to as the inactive metabolite of GLP‐1. Recently, however, GLP‐1(9‐36)amide was suggested to have extrapancreatic insulin‐like actions (insulinomimetic action) on insulin‐sensitive tissues such as heart, vasculature, and liver (6, 7). Infusion of GLP‐1(9‐36)amide in obese insulin‐resistant subjects was noted to acutely lower hepatic glucose production (8).…”

“…Recently, however, GLP‐1(9‐36)amide was suggested to have extrapancreatic insulin‐like actions (insulinomimetic action) on insulin‐sensitive tissues such as heart, vasculature, and liver (6, 7). Infusion of GLP‐1(9‐36)amide in obese insulin‐resistant subjects was noted to acutely lower hepatic glucose production (8). GLP‐1(9‐36) amide was also demonstrated to inhibit glucose production by the inhibition of gluconeogenesis in isolated mouse hepatocytes in vitro (9), and in vivo , GLP‐1(9‐36) amide metabolite attenuated diabetes in diet‐induced obese mice (10).…”

Contribution of Macrophage Polarization to Metabolic Diseases

“…It has also been reported that a GLP-1R agonist improved steatohepatitis in a murine NASH model by regulating hepatic fatty acid metabolism 49) . In addition, treatment with a GLP-1R agonist decreased weight gain in obese mice by activating fat metabolism 50) , and in obese women, it reduced the body mass index (BMI) 51) . Furthermore, a GLP-1R agonist reduced serum concentrations of TNF-, IL-1 , IL-6, and soluble CD163, all of which are known macrophagederived inflammatory molecules in patients with type 2 diabetes mellitus 52) .…”