Muscle-specific transgenic complementation of GLUT4-deficient mice. Effects on glucose but not lipid metabolism.

Abstract

We have taken the approach of introducing the muscle-specific myosin light chain (MLC)-GLUT4 transgene into the GLUT4-null background to assess the relative role of muscle and adipose tissue GLUT4 in the etiology of the GLUT4-null phenotype. The resulting MLC-GLUT4-null mice express GLUT4 predominantly in the fast-twitch extensor digitorum longus (EDL) muscle. GLUT4 is nearly absent in female white adipose tissue (WAT) and slowtwitch soleus muscle of both sexes of MLC-GLUT4-null mice. GLUT4 content in male MLC-GLUT4-null WAT is 20% of that in control mice. In transgenically complemented EDL muscle, 2-deoxyglucose (2-DOG) uptake was restored to normal (male) or above normal (female) levels. In contrast, 2-DOG uptake in slow-twitch soleus muscle of MLC-GLUT4-null mice was not normalized. With the normalization of glucose uptake in fast-twitch skeletal muscle, whole body insulin action was restored in MLC-GLUT4-null mice, as shown by the results of the insulin tolerance test. These results demonstrate that skeletal muscle GLUT4 is a major regulator of skeletal muscle and whole body glucose metabolism. Despite normal skeletal muscle glucose uptake and insulin action, the MLC-GLUT4-null mice exhibited decreased adipose tissue deposits, adipocyte size, and fed plasma FFA levels that are characteristic of GLUT4-null mice. Together these results indicate that the defects in skeletal muscle and whole body glucose metabolism and adipose tissue in GLUT4-null mice arise independently. ( J. Clin. Invest. 1997. 100:671-677.) Key words: GLUT4 • transgenic mice • knockout mice • glucose metabolism • skeletal muscle

GLUT4Gene Regulation and Manipulation

“…Like GLUT4 null mice, MLC-GLUT4 null mice weigh approximately 20% less than controls and exhibit significantly decreased fed serum free fatty acid levels (37). Further, MLC-GLUT4 null mice also have significantly reduced inguinal fat pads and adipose cells compared with controls.…”

“…The muscle-specific MLC-GLUT4 transgene (26) was mated into the genetic background of GLUT4 null mice to generate a population of MLC-GLUT4 null mice (37). MLC-GLUT4 null mice have restored GLUT4 expression in glycolytic muscle such as EDL but not in oxidative muscles like soleus.…”

Control of body weight: a physiologic and transgenic perspective

“…The glucose transporter 4 (GLUT4) is primarily expressed in tissues responding to insulin-stimulated glucose uptake such as WAT, BAT, skeletal and cardiac muscle [10]. Two transgenic models overexpressing GLUT4 specifically in adipose tissue [32] or in fast-twitch skeletal muscle [162] have been generated. GLUT4-null mice have also been produced [79,163] and intercrossed with the animals overexpressing GLUT4 in skeletal muscle fibres to yield a line that expresses GLUT4 only in fast-twitch muscles [162].…”

“…Two transgenic models overexpressing GLUT4 specifically in adipose tissue [32] or in fast-twitch skeletal muscle [162] have been generated. GLUT4-null mice have also been produced [79,163] and intercrossed with the animals overexpressing GLUT4 in skeletal muscle fibres to yield a line that expresses GLUT4 only in fast-twitch muscles [162]. Increased body weight and total lipid content due to adipose cell hyperplasia together with an enhanced glucose disposal were observed in transgenic mice overexpressing GLUT4 selectively in adipose tissue [32].…”

“…Increased body weight and total lipid content due to adipose cell hyperplasia together with an enhanced glucose disposal were observed in transgenic mice overexpressing GLUT4 selectively in adipose tissue [32]. Overexpression of GLUT4 specifically in fast-twitch muscles did not affect body weight but lead to decreased fasting glycaemia and an increase in insulin-stimulated glucose clearance [162]. GLUT4 −/− mice are characterised by a decreased body weight due to a marked WAT reduction accompanied by normoglycaemia and a normal response to a glucose load [79].…”