A novel PPARα agonist ameliorates insulin resistance in dogs fed a high-fat diet

Abstract

Tsunoda M, Kobayashi N, Ide T, Utsumi M, Nagasawa M, Murakami K. A novel PPAR␣ agonist ameliorates insulin resistance in dogs fed a high-fat diet. Am J Physiol Endocrinol Metab 294: E833-E840, 2008. First published January 22, 2008 doi:10.1152/ajpendo.00627.2007.-Agonism of peroxisome proliferator-activated receptor (PPAR) ␣, a key regulator of lipid metabolism, leads to amelioration of lipid abnormalities in dyslipidemic patients. However, whether PPAR␣ agonism is an effective form of therapy for obesity-related insulin resistance associated with lipid abnormalities is unclear. The present study investigated the effects of a potent and subtype-selective PPAR␣ agonist, KRP-101, in a nonrodent insulin-resistant animal model under pair-fed conditions. Beagle dogs were fed a high-fat diet for 24 wk to induce insulin resistance. During the final 12 wk, 0.03 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 KRP-101 (n ϭ 5) or vehicle (n ϭ 5) was administered orally once a day. KRP-101 administration resulted in a significantly lower weight of overall visceral fat, which is associated with increased adiponectin and decreased leptin in serum. KRP-101 administration improved hyperglycemia and hyperinsulinemia as well as dyslipidemia in dogs fed a high-fat diet. Oral glucose tolerance test showed that KRP-101 administration improved glucose intolerance. The KRP-101 group showed a markedly lower hepatic triglyceride concentration. Lipid oxidation was increased in the liver and skeletal muscles of the KRP-101 group. These findings in the dog model suggest that the use of potent and subtype-selective PPAR␣ agonists as a potentially relevant therapeutic approach to treat human insulin resistance associated with visceral obesity.

Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

“…These findings are consistent with those of previous studies showing that lipid accumulation in kidneys promotes glomerulosclerosis through the low-density lipoprotein-receptor in mesangial cells, through macrophage chemotaxis, increased production of fibrotic cytokines and direct podocyte injury through oxidative stress. [40][41][42][43][44] These relationships are also supported by our finding that more lipid accumulated in the kidneys of SHR-HF rats than in those of WKY-HF rats, and they had more severe glomerulosclerosis and inflammatory cell infiltration. Oxidative stress is both a cause and a consequence of hypertension and constitutes an additional stimulus for sodium retention in kidneys.…”

Hepatic Glycogen Supercompensation Activates AMP-Activated Protein Kinase, Impairs Insulin Signaling, and Reduces Glycogen Deposition in the Liver

“…Real-time PCR was performed using canine-specific primers for GK (25) fatty acid synthase (FAS) (26), carnitine palmitoyltransferase (CPT) (27), and hypoxanthine phosphoribosyl transferase-1 (25). The PCR protocol consisted of a denaturing cycle at 95°C for 2 min followed by a 35-cycle amplification step (95°C for 30 s, 55–60°C for 30 s, 72°C for 30 s).…”

Targeting Peroxisome Proliferator-Activated Receptors Using Thiazolidinediones: Strategy for Design of Novel Antidiabetic Drugs

“…BMS631707 (7) possess a characteristic conformationally restricted azetidinone ring linked to the carboxylic acid group, which aids the drug to occupy a new hydrophobic pocket. KRP101 (8) has a typical topology of a PPAR α agonist as explained earlier [41]. Carboxylic acid head group is linked to an aromatic ring in AVE8134 (9) structure [42].…”