A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain - PubMed (original) (raw)

A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain

François R Jornayvaz et al. Am J Physiol Endocrinol Metab. 2010 Nov.

Abstract

Low-carbohydrate, high-fat ketogenic diets (KD) have been suggested to be more effective in promoting weight loss than conventional caloric restriction, whereas their effect on hepatic glucose and lipid metabolism and the mechanisms by which they may promote weight loss remain controversial. The aim of this study was to explore the role of KD on liver and muscle insulin sensitivity, hepatic lipid metabolism, energy expenditure, and food intake. Using hyperinsulinemic-euglycemic clamps, we studied insulin action in mice fed a KD or regular chow (RC). Body composition was assessed by ¹H magnetic resonance spectroscopy. Despite being 15% lighter (P < 0.001) than RC-fed mice because of a 17% increase in energy expenditure (P < 0.001), KD-fed mice manifested severe hepatic insulin resistance, as reflected by decreased suppression (0% vs. 100% in RC-fed mice, P < 0.01) of endogenous glucose production during the clamp. Hepatic insulin resistance could be attributed to a 350% increase in hepatic diacylglycerol content (P < 0.001), resulting in increased activation of PKCε (P < 0.05) and decreased insulin receptor substrate-2 tyrosine phosphorylation (P < 0.01). Food intake was 56% (P < 0.001) lower in KD-fed mice, despite similar caloric intake, and could partly be attributed to a more than threefold increase (P < 0.05) in plasma N-acylphosphatidylethanolamine concentrations. In conclusion, despite preventing weight gain in mice, KD induces hepatic insulin resistance secondary to increased hepatic diacylglycerol content. Given the key role of nonalcoholic fatty liver disease in the development of type 2 diabetes and the widespread use of KD for the treatment of obesity, these results may have potentially important clinical implications.

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Figures

Fig. 1.

Fig. 1.

Ketogenic diet (KD) causes hepatic insulin resistance in mice. A: euglycemia (100–120 mg/dl) was maintained throughout the clamp in mice fed KD and those fed regular chow (RC). B: basal endogenous glucose production was similar between groups. C: glucose infusion rates were significantly lower in KD-fed mice. D: ability of insulin to suppress clamp endogenous glucose production was significantly impaired in KD-fed mice. E and F: glycolysis and glycogen synthesis were similar between groups. Values are means ± SE (n = 9 per group). **P < 0.01; ***P < 0.001 vs. RC.

Fig. 2.

Fig. 2.

KD causes a decrease in insulin-stimulated whole body glucose disposal. A: insulin-stimulated whole body glucose disposal was significantly lower in KD-fed mice (n = 9 per group). This lower level of insulin-stimulated whole body glucose disposal was due to decreased heart muscle glucose uptake (B), as well as decreased brown adipose tissue (BAT) glucose uptake (C); there was no difference in muscle [gastrocnemius (D) and quadriceps (QD, E)] or white adipose tissue (WAT, F) glucose uptake (n = 8 per group). Values are means ± SE. *P < 0.05; **P < 0.01 vs. RC.

Fig. 3.

Fig. 3.

KD increases liver lipid metabolites and impairs hepatic insulin signaling. A: histological evidence of nonalcoholic fatty liver disease in KD-fed mice with microvesicular pattern lipid infiltration (hematoxylin and eosin staining, ×100 magnification). B–D: increase in liver lipid metabolites. Triglycerides (B), diacylglycerol (DAG, C), and ceramide (D) were significantly increased in KD-fed mice (n = 6 per group). Consequently, in KD-fed mice, PKCε was significantly translocated to the membrane (F), and insulin receptor substrate-2 (IRS-2) tyrosine phosphorylation was decreased (G) (n = 4–5 per group). Muscle (gastrocnemius) triglyceride content (E) was not different between groups. Values are means ± SE (n = 6 per group). *P < 0.05; **P < 0.01; ***P < 0.001 vs. RC.

Fig. 4.

Fig. 4.

KD modifies gene expression regulating hepatic glucose metabolism. A: liver mRNA expression was not different for glucose-6-phosphatase (G6Pase), phospho_enol_pyruvate carboxykinase (PEPCK), and pyruvate carboxylase (PC), whereas fibroblast growth factor-21 (FGF21) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA were significantly increased (n = 6 per group). PC protein level (B) was significantly increased in KD-fed mice, whereas PEPCK protein level (C) was not different (n = 4–5 per group). Values are means ± SE. *P < 0.05 vs. RC.

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