Hypocaloric high-protein diet improves fatty liver and hypertriglyceridemia in sucrose-fed obese rats via two pathways

Abstract

The mechanism by which replacement of some dietary carbohydrates with protein during weight loss favors lipid metabolism remains obscure. In this study, we investigated the effect of an energy-restricted, high-protein/low-carbohydrate diet on lipid metabolism in obese rats. High-sucrose-induced obese rats were assigned randomly to one of two energy-restricted dietary interventions: a carbohydrate-based control diet (CD) or a high-protein diet (HPD). Lean rats of the same age were assigned as normal control. There was significantly greater improvement in fatty liver and hypertriglyceridemia with the HPD diet relative to the CD diet. Expression of genes regulated by fibroblast growth factor-21 (FGF21) and involved in liver lipolysis and lipid utilitization, such as lipase and acyl-CoA oxidase, increased in obese rats fed the HPD. Furthermore, there was an inverse correlation between levels of FGF21 gene expression (regulated by glucagon/insulin balance) and increased triglyceride concentrations in liver from obese rats. Expression of hepatic stearoyl-CoA desaturase-1 (SCD1), regulated primarily by the dietary carbohydrate, was also markedly reduced in the HPD group (similar to plasma triglyceride levels in fasting animals) relative to the CD group. In conclusion, a hypocaloric high-protein diet improves fatty liver and hypertriglyceridemia effectively relative to a carbohydrate diet. The two cellular pathways at work behind these benefits include stimulation of hepatic lipolysis and lipid utilization mediated by FGF21 and reduction of hepatic VLDL-TG production by SCD1 regulation.

Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis?

“…Recently, it has been shown that glucagon modulates Fgf-21 expression [12][13][14][15]. Here, we extend these observations by reporting for the first time that glucagon increases, independently of endogenous insulin levels, circulating levels of FGF-21 in humans and rodents.…”

“…In contrast, removal of exogenous insulin in humans with type 1 diabetes resulted in an approximately 10% increase in plasma FGF-21 [18], suggesting that insulin reduces FGF-21. In addition, insulin inhibited glucagonstimulated Fgf-21 expression in rat hepatocytes [12].…”

“…* p <0.05, ** p <0.01 and *** p <0.001 vs vehicle-treated groups (indicated as -). Each experiment was repeated three times The increase of FGF-21 plasma concentration by exogenous glucagon regardless of endogenous insulin production is somehow intriguing, in view of the contradictory results of earlier studies showing that insulin regulates FGF-21 [12,15,17,30]. Exogenous insulin increased plasma FGF-21 and Fgf-21 mRNA expression in skeletal muscle in humans [30].…”

“…In contrast, circulating FGF-21 increased after insulin was removed from patients with type 1 diabetes [18]. In vitro, insulin inhibited glucagon-stimulated hepatic Fgf-21 expression in rodents [12].…”

“…In rodents glucagon seems to stimulate Fgf-21 expression in vitro and in vivo [12][13][14][15], and these effects are somewhat augmented by NEFA [15]. However, another study reported that glucagon fails to stimulate hepatic Fgf-21 mRNA expression in rodents [16].…”