Acute (24 h) activation of peroxisome proliferator-activated receptor-alpha (PPARalpha) reverses high-fat feeding-induced insulin hypersecretion in vivo and in perifused pancreatic islets

Abstract

Abnormal depletion or accumulation of islet lipid may be important for the development of pancreatic cell failure. Long-term lipid sensing by cells may be co-ordinated via peroxisome proliferator-activated receptors (PPARs). We investigated whether PPAR activation in vivo for 24 h affects basal and glucose-stimulated insulin secretion in vivo after intravenous glucose administration and ex vivo in isolated perifused islets. Insulin secretion after intravenous glucose challenge was greatly increased by high-fat feeding (4 weeks) but glucose tolerance was minimally perturbed, demonstrating insulin hypersecretion compensated for insulin resistance. The effect of high-fat feeding to enhance glucose-stimulated insulin secretion was retained in perifused islets demonstrating a stable, long-term effect of high-fat feeding to potentiate islet glucose stimulussecretion coupling. Treatment of high-fat-fed rats with WY14,643 for 24 h reversed insulin hypersecretion in vivo without impairing glucose tolerance, suggesting improved insulin action, and ex vivo in perfused islets. PPAR activation only affected hypersecretion of insulin since glucose-stimulated insulin secretion was unaffected by WY14,643 treatment in vivo in control rats or in perifused islets from control rats. Our data demonstrate that activation of PPAR for 24 h can oppose insulin hypersecretion elicited by high-fat feeding via stable long-term effects exerted on islet function. PPAR could, therefore, participate in ameliorating abnormal glucose homeostasis and hyperinsulinaemia in dietary insulin resistance via modulation of islet function, extending the established requirement for PPAR for normal islet lipid homeostasis.

Interactive influences of peroxisome proliferator-activated receptor α activation and glucocorticoids on pancreatic beta cell compensation in insulin resistance induced by dietary saturated fat in the rat

“…Increased dietary saturated fat can also elicit the development of insulin resistance [10][11][12] (reviewed in [13,14]). However, contrasting with the facilitatory role of PPARα in the induction of hepatic insulin resistance in response to glucocorticoids, PPARα activation improves insulin sensitivity in the high dietary fat model of insulin resistance [15,16]. The differences in the influence of PPARα activation on insulin resistance induced by glucocorticoids and that induced by high-saturated-fat feeding may reflect the underlying mechanisms invoking insulin resistance in these two states, namely a more hepatocentric action in glucocorticoid-induced insulin resistance, contrasting with a wider influence of high-fat feeding to induce tissue lipid accumulation with resultant dysregulation of insulin signalling.…”

“…Sham operations involving incision and manipulation under anaesthesia identical to the procedure for implantation of the osmotic minipump were undertaken on a second (control) group of rats. The PPARα agonist WY14643 (or vehicle) was administered as a single intraperitoneal injection (50 mg kg −1 body weight), and rats were sampled after 24 h [15,22] (HF-WY and HF-DEX-WY groups). We used acute (24 h) exposure to WY14643, rather than longer term repeated administration over several days, since we have previously demonstrated that activation of PPARα by a single bolus dose of WY14643 opposes insulin hypersecretion elicited by high-fat feeding [15], and therefore the present study can be compared directly with our earlier studies.…”

“…Free islets were collected under a dissecting microscope with a 20 μl pipette into HEPES-buffered Hanks' balanced salt solution containing 5% BSA. Insulin release from freshly isolated islets was measured in a perifusion system as described [15,24]. In this system, 50 islets were housed in small chambers on Millicell culture plate inserts (Sigma, Poole, Dorset, UK).…”

“…Importantly, there is increasing evidence that long-term lipid sensing by the pancreatic beta cell could be coordinated through the expression and/or activity of PPARα [17,18] (reviewed in [19,20]). We have recently established that activation of PPARα can oppose insulin hypersecretion elicited by high-fat feeding via stable long-term effects exerted on islet function [15].…”

Peroxisome proliferator-activated receptor α (PPARα) protects against oleate-induced INS-1E beta cell dysfunction by preserving carbohydrate metabolism

“…Recent studies indicate a new role for PPARα in beta cells, that of protecting against fatty acid-induced dysfunction [20][21][22]. In rats, it was observed that activation of PPARα for 24 h can reverse the insulin hypersecretion induced by high-fat feeding [23]. In ob/ob mice, glucose intolerance is aggravated by the absence of PPARα, correlating with reduced glucose-stimulated insulin secretion in isolated islets [21].…”