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

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.

Neuroactive steroid changes in response to challenge with the panicogenic agent pentagastrin.

BACKGROUND: Female hormones and female hormone derivatives, including neuroactive steroids (NASs) have been suspected to play a role in the pathophysiology of panic disorder (PD). The panicogenic agent CO(2) has been shown to induce a delayed release of NASs in both brain and plasma of rats. In the present study, we measured NASs plasma levels in response to challenge with another panicogenic agent, pentagastrin, and assessed the effect of ethynil estradiol (EE) pretreatment. METHODS: A double-blind cross-over placebo-controlled design with randomization of the order of a three day pretreatment of EE (50 microg/day) or placebo was used to assess the effect of a 30 microg iv bolus injection of pentagastrin on the release of allopregnanolone (ALLO) and dehydroepiandrosterone (DHEA) into plasma in 15 male PD patients and 10 male healthy volunteers (HV). RESULTS: After pentagastrin challenge there was a significant release of DHEA and a trend for the release of ALLO. EE pretreatment did not affect the pentagastrin-induced panic response or NAS release. CONCLUSIONS: Pentagastrin induced release of NASs into plasma, the purpose of which remains to be determined.

Pentagastrin-induced hemoconcentration in healthy volunteers and patients with panic disorder: effect of pretreatment with ethinyl estradiol.

Panic disorder has been associated with both an increased risk of coronary events as well as an increased risk of stroke. Hemoconcentration, with both a decrease in plasma volume and an increase in plasma viscosity, is a possible contributor to the risk of acute ischemic events. Our objectives were to demonstrate the process of hemoconcentration in response to induced panic symptoms and to assess the effect of pretreatment with ethinyl estradiol on panic-induced hemoconcentration. Fifteen male patients with panic disorder and 10 male healthy volunteers were included in a double-blind cross-over placebo-controlled design consisting of two injections of pentagastrin following randomized pretreatment with placebo and ethinyl estradiol. Plasma levels of hematocrit and hemoglobin were assessed at baseline and post-injections, and used to calculate an indirect estimation of the change in plasma volume. Pentagastrin-induced panic symptoms were associated with a mean decrease in plasma volume of 4.8% in the placebo pretreatment condition. Pretreatment with ethinyl estradiol attenuated this effect. The acute hemoconcentration observed in relation to pentagastrin-induced panic symptoms may be relevant to the increased risk of stroke and acute coronary events found in patients with panic disorder.

Pentagastrin-induced release of free fatty acids in healthy volunteers and patients with panic disorder: effect of pretreatment with ethinyl estradiol.

OBJECTIVE: The primary objective of this study was to assess whether pentagastrin-induced panic symptoms are associated with release of free fatty acids (FFAs) in a manner that could explain the mechanism of correlations observed between serum cholesterol levels and frequency and severity of panic attacks in patients with panic disorder (PD). A secondary objective was to assess whether pretreatment with ethinyl estradiol (EE) attenuates pentagastrin-induced release of FFAs. METHODS: A double-blind, crossover, placebo-controlled study was conducted in which patients with PD and healthy volunteers received 2 injections of pentagastrin, 7-10 days apart, with randomization of the order of pretreatment with placebo and EE. RESULTS: We found a statistically significant, time-dependent release of FFAs in response to pentagastrin challenge. However, this release of FFAs was not attenuated by pretreatment with EE. CONCLUSIONS: These results support the hypothesis that release of FFAs in association with panic attacks occurs in a manner similar to the stress-induced lipolysis model. This suggests a possible mechanism for the elevated serum cholesterol levels observed in patients with PD. However, the occurrence of a delayed increase in low-density lipoprotein (LDL) cholesterol following induction of a panic attack remains to be tested in studiesincorporating a placebo injection visit and timed measurements of LDL cholesterol.