Redistribution of Glucose From Skeletal Muscle to Adipose Tissue During Catch-Up Fat

Abstract

Catch-up growth, a risk factor for later obesity, type 2 diabetes, and cardiovascular diseases, is characterized by hyperinsulinemia and an accelerated rate for recovering fat mass, i.e., catch-up fat. To identify potential mechanisms in the link between hyperinsulinemia and catch-up fat during catch-up growth, we studied the in vivo action of insulin on glucose utilization in skeletal muscle and adipose tissue in a previously described rat model of weight recovery exhibiting catch-up fat caused by suppressed thermogenesis per se. To do this, we used euglycemic-hyperinsulinemic clamps associated with the labeled 2-deoxy-glucose technique. After 1 week of isocaloric refeeding, when body fat, circulating free fatty acids, or intramyocellular lipids in refed animals had not yet exceeded those of controls, insulin-stimulated glucose utilization in refed animals was lower in skeletal muscles (by 20 -43%) but higher in white adipose tissues (by two-to threefold). Furthermore, fatty acid synthase activity was higher in adipose tissues from refed animals than from fed controls. These results suggest that suppressed thermogenesis for the purpose of sparing glucose for catch-up fat, via the coordinated induction of skeletal muscle insulin resistance and adipose tissue insulin hyperresponsiveness, might be a central event in the link between catch-up growth, hyperinsulinemia and risks for later metabolic syndrome.

Hepatic mitochondrial energetics during catch-up fat after caloric restriction

“…In addition, the findings from indirect calorimetry of NPRQ values greater than 1 suggest that the increased lipid deposition typical of refed rats is partly the result of the occurrence of a higher rate of de novo lipogenesis in refed rats than in controls. This result is well in agreement with the "glucose redistribution hypothesis" [7,21], according to which the insulin-resistant state of skeletal muscle found in refed rats is of central importance in sparing glucose that can be diverted toward de novo lipogenesis and fat storage in adipose tissue. Indeed, a higher FAS activity-and hence de novo lipogenic capacity-has been reported in white adipose tissues of refed rats relative to controls [7,21].…”

“…Rats showing catch-up fat exhibit diminished subsarcolemmal mitochondrial mass and oxidative capacity in skeletal muscle [6]. In addition, in vivo insulin-stimulated glucose utilization has been shown to be lower in skeletal muscle but higher in adipose tissue of refed animals showing catch-up fat, thereby suggesting a redistribution of glucose utilization away from skeletal muscle toward de novo lipogenesis and fat storage in adipose tissue [7].…”

Altered Skeletal Muscle Subsarcolemmal Mitochondrial Compartment During Catch-Up Fat After Caloric Restriction

“…The fact that after 1 week of refeeding, the HOMA index, but not body fat or plasma NEFA, was higher in the refed animals than in controls suggests that the state of insulin resistance during refeeding precedes the development of excess adiposity or elevations in circulating NEFA. Using this same rat model, we previously reported that after 1 week of refeeding, i.e., at a time point when their body fat, plasma NEFA, and intramyocellular lipids had not exceeded those of controls, the refed rats showed higher plasma insulin after a glucose load (12) and a lower in vivo insulin-stimulated glucose utilization in skeletal muscle, as assessed by hyperinsulinemic-euglycemic clamp techniques (13). Taken together, these previous and present studies suggest that during weight recovery, the state of suppressed thermogenesis per se may have a direct impact on the development of skeletal muscle insulin resistance.…”

“…To what extent an increased ROS levels in skeletal muscle might be causative or consequential to the state of insulin resistance during refeeding is not known. However, the integration of data from our present and previous studies (12,13) underscores a potential link between diminished SS mitochondrial energetics, altered mitochondrial ROS levels, and insulin resistance in rats showing catch-up fat as a result of suppressed thermogenesis.…”

“…Furthermore, the use of euglycemic-hyperinsulinemic clamp revealed that in vivo insulin-stimulated glucose utilization is lower in skeletal muscles from refed than in those from control animals (13). Because skeletal muscle is an important contributor to whole-body energy expenditure and a major site for insulin-stimulated glucose disposal, the possibility arises that suppressed thermogenesis in this tissue would result in a reduction in glucose utilization, thereby leading to compensatory hyperinsulinemia.…”