Effect of GLP-1 on Lipid Metabolism in Human Adipocytes

Abstract

We have studied the effect of several doses of GLP-1, compared to that of insulin and glucagons, on lipogenesis, lipolysis and cAMP cellular content, in human adipocytes isolated from normal subjects. In human adipocytes, GLP-1 exerts a dual action, depending upon the dose, on lipid metabolism, being lipogenic at low concentrations of the peptide (ED50, 10(-12) M), and lipolytic only at doses 10-100 times higher (ED50, 10(-10) M); both effects are time- and GLP-1 concentration-dependent. The GLP-1 lipogenic effect is equal in magnitude to that of equimolar amounts of insulin; both hormones apparently act synergically, and their respective action is abolished by glucagon. The lipolytic effect of GLP-1 is comparable to that of glucagon, apparently additive to it, and the stimulated value induced by either one is neutralized by the presence of insulin. In the absence of IBMX, GLP-1, at 10(-13) and 10(-12) M, only lipogenic doses, does not modify the cellular content of cAMP, while from 10(-11) M to 10(-9) M, also lipolytic concentrations, it has an increasing effect; in the presence of IBMX, GLP-1 at already 10(-12) M increased the cellular cAMP content. In human adipocytes, GLP-1 shows glucagon- and also insulin-like effects on lipid metabolism, suggesting the possibility of GLP-1 activating two distinct receptors, one of them similar or equal to the pancreatic one, accounting cAMP as a second messenger only for the lipolytic action of the peptide.

Direct Control of Peripheral Lipid Deposition by CNS GLP-1 Receptor Signaling Is Mediated by the Sympathetic Nervous System and Blunted in Diet-Induced Obesity

“…However, in contrast to WAT, the effects of CNS GLP-1 on hepatic lipid deposition are dependent on and presumably secondary to reduced nutrient intake. Although GLP-1-R has not been found in WAT (Bullock et al, 1996), several studies have suggested that GLP-1 can directly act on adipocyte metabolism, although the molecular mechanisms modulating those peripheral actions are unknown (Ruiz-Grande et al, 1992;Mérida et al, 1993;Valverde et al, 1993;Bertin et al, 2001;Villanueva-Peñacarrillo et al, 2001;Sancho et al, 2005Sancho et al, , 2006. We have excluded the possibility that increased peripheral GLP-1 levels contributed to the observed effects, because peripheral infusion of the identical amount of GLP-1 failed to trigger any effects.…”

Exendin-4 Potently Decreases Ghrelin Levels in Fasting Rats

“…Whereas ghrelin increases food intake (1,2), gastric acid secretion and motility (5), and fat deposition (1), GLP-1 reduces food intake (12,13), gastric acid secretion (14), and gastric emptying (15) and displays lipolytic effects (16). An inverse relationship between GLP-1 and ghrelin levels has been demonstrated after a standard glucose tolerance test in humans (17).…”

Preclinical and Clinical Data on Extraglycemic Effects of GLP-1 Receptor Agonists

“…GLP-1 has been shown to stimulate lypolysis in rat [102] and human [103] adipocytes. In a small study of 20 patients with type 2 diabetes, a continuous 6-week infusion of GLP-1 produced reductions in fasting and 8-hour mean concentrations of free fatty acids [104].…”

“…Treatment with GLP-1 at supraphysiologic concentrations resulted in increased femoral arterial blood flow correlated with whole- The beneficial effects of GLP-1 on CV parameters may also occur indirectly through GLP-1-mediated improvements in fatty free acid levels and glucose disposal. GLP-1 has been shown to stimulate lypolysis in rat [102] and human [103] adipocytes. In a small study of 20 patients with type 2 diabetes, a continuous 6-week infusion of GLP-1 produced reductions in fasting and 8-hour mean concentrations of free fatty acids [104].…”