LEPTIN TREATMENT INCREASES GLUT4 BUT NOT GLUT1 PROTEIN CONCENTRATION IN INSULIN-RESISTANT MUSCLE

Abstract

We have recently shown chronic leptin administration to improve insulin-stimulated skeletal muscle glucose transport in insulin-resistant skeletal muscle (Yaspelkis et al., AJP, in press), but did not address if basal glucose transport was affected. Therefore, the aim of this investigation was to determine if non-insulin stimulated (basal) glucose transport is improved in insulin-resistant skeletal muscle in response to chronic leptin administration. Twenty-four male Sprague Dawley rats were divided into one of two groups: 1) Normal diet (n = 8) or 2) High-Fat diet (n = 16). Normal diet (CON) animals received standard rat chow for 12 weeks while the other animals were provided a high fat diet to induce skeletal muscle insulin-resistance. Twelve days prior to hind limb perfusions, the high fat diet animals were further subdivided: High Fat (HF) (n = 8) or High Fat-Leptin (HF-LEP) (n = 8). During this 12 d period, HF-LEP animals were injected with leptin (5 mg leptin/kg) s.c. at 0800 and 1800 h daily while the CON and HF animals received vehicle (PBS). All animals were prepared for and subjected to bind limb perfusion following the 12 d treatment period to determine rates of basal skeletal muscle 3-O-methyl-D-glucose (3-MG) transport. Leptin administration did not alter rates of 3-MG transport under basal conditions in CON, HF-LEP or HF groups. Although total and plasma membrane (PM) GLUT4 protein concentration were significantly (p < 0.05) reduced in the skeletal muscle of the HF animals, this did not affect rates of basal glucose transport. It appeared that rates of 3-MG transport were unaffected due to the basal glucose transporter protein concentration, GLUT1, being similar among groups. Of interest, however, was that 12d of leptin treatment normalized both total and PM GLUT4 protein concentration in the skeletal muscle of the HF-LEP animals. The results of this investigation indicate that while a high fat diet and subsequent leptin treatment alter expression of the insulin-responsive glucose transporter (GLUT4) in insulin-resistant skeletal muscle, no effect is observed on non-insulin-stimulated glucose transport or GLUT1 protein concentration in response to a high fat diet or leptin administration. This suggests the expression of these two glucose transporter isoforms may be differentially regulated. Supported by NIH GM 48680