Partial Body Mass Recovery After Caloric Restriction Abolishes Improved Glucose Tolerance in Obese, Insulin Resistant Rats

Abstract

Caloric restriction, among other behavioral interventions, has demonstrated benefits on improving glycemic control in obesity-associated diabetic subjects. However, an acute and severe intervention without proper maintenance could reverse the initial benefits, with additional metabolic derangements. To assess the effects of an acute caloric restriction in a metabolic syndrome model, a cohort of 15-week old Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats were calorie restricted (CR: 50% × 10 days) with or without a 10-day body mass (BM) recovery period, along with their respective ad libitum controls. An oral glucose tolerance test (oGTT) was performed after CR and BM recovery. Both strains had higher rates of mass gain during recovery vs. ad lib controls; however, the regain was partial (ca. 50% of ad lib controls) over the measurement period. Retroperitoneal and epididymal adipose masses decreased 30% (8.8 g, P < 0.001) in OLETF; however, this loss only accounted for 11.5% of the total BM loss. CR decreased blood glucose AUC 16% in LETO and 19% in OLETF, without significant decreases in insulin. Following CR, hepatic expression of the gluconeogenic enzyme, PEPCK, was reduced 55% in OLETF compared to LETO, and plasma triglycerides (TG) decreased 86%. Acute CR induced improvements in glucose tolerance and TG suggestive of improvements in metabolism; however, partial recovery of BM following CR abolished the improvement in glucose tolerance. The present study highlights the importance of proper maintenance of BM after CR as only partial recovery of the lost BM reversed benefits of the initial mass loss.

Mass Recovery following Caloric Restriction Reverses Lipolysis and Proteolysis, but not Gluconeogenesis, in Insulin Resistant OLETF Rats

“…This impairment has been previously described in obese, diabetic rats secondary to hyperphagia and an impairment in the leptin receptor [3], and in T2D patients compared to healthy subjects [31]. The improvement in IRI in OLETF with CR [18] substantiates this data suggesting that CR improves glucose metabolism via enhanced TCA cycle activity. However, in the OLETF the impairment in basal glucose metabolism is likely induced by impaired glycolysis because basal levels of 3-phosphoglycerate were lower in OLETF compared to LETO.…”

“…Details of the current study have been published previously [18] and summarized in Figure 1. The current study complements the previous data by using metabolomics approaches to examine the shifts in metabolism associated with changes in body mass induced by CR and refeeding.…”

“…Oral glucose tolerance tests (oGTT) were performed as previously reported [18] and insulin resistance index (IRI) was calculated as previously described [13] and reported [18]. Data were used here to correlate the shifts in metabolites with IRI.…”

“…Details of blood sample and tissue collections have been previously reported [18]. Briefly, animals were anesthetized after an overnight fasting with a 100 mg/kg i.p.…”

“…Pearson correlations were calculated for parameters previously reported [18]. Johnson transformed body mass, IRI, and retroperitoneal and epididymal adipose masses were treated as independent variables and Johnson transformed metabolites were treated as dependent variables.…”