Preserved direct hepatic insulin action in rats with diet-induced hepatic steatosis

Buettner, Roland; Ottinger, Iris; Schölmerich, Jürgen; Bollheimer, Leo Cornelius

doi:10.1152/ajpendo.00453.2003

Cited by 40 publications

(32 citation statements)

References 46 publications

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“…As described previously, hepatic steatosis was induced by the HF-L diet (Buettner et al 2004). Histologic examination of the liver did not reveal signs of inflammation or distinct fibrotic changes.…”

Section: Discussionmentioning

confidence: 58%

Defining high-fat-diet rat models: metabolic and molecular effects of different fat types

Buettner¹,

Parhofer²,

Woenckhaus³

et al. 2006

Journal of Molecular Endocrinology

598

410

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High-fat (HF)-diet rodent models have contributed significantly to the analysis of the pathophysiology of the insulin resistance syndrome, but their phenotype varies distinctly between different studies. Here, we have systematically compared the metabolic and molecular effects of different HF with varying fatty acid compositions. Male Wistar rats were fed HF diets (42% energy; fat sources: HF-L -lard; HF-O -olive oil; HF-C -coconut fat; HF-F -fish oil). Weight, food intake, whole-body insulin tolerance and plasma parameters of glucose and lipid metabolism were measured during a 12-week diet course. Liver histologies and hepatic gene expression profiles, using Affymetrix GeneChips, were obtained. HF-L and HF-O fed rats showed the most pronounced obesity and insulin resistance; insulin sensitivity in HF-C and HF-F was close to normal. Plasma -3 polyunsaturated fatty acid ( -3-PUFA) and saturated fatty acid (C 12 -C 14 , SFA) levels were elevated in HF-F and HF-C animals respectively. The liver histologies showed hepatic steatosis in HF-L, HF-O and HF-C without major inflammation. Hepatic SREBP1c-dependent genes were upregulated in these diets, whereas PPAR -dependent genes were predominantly upregulated in HF-F fed rats. We detected classical HF effects only in diets based on lard and olive oil (mainly long-chain, saturated (LC-SFA) and monounsaturated fatty acids (MUFA)). PUFA-or MC-SFA-rich diets did not induce insulin resistance. Diets based on LC-SFA and MUFA induced hepatic steatosis with SREBP1c activation. This points to an intact transcriptional hepatic insulin effect despite resistance to insulin's metabolic actions.

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Section: Discussionmentioning

confidence: 58%

Defining high-fat-diet rat models: metabolic and molecular effects of different fat types

Buettner¹,

Parhofer²,

Woenckhaus³

et al. 2006

Journal of Molecular Endocrinology

598

410

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“…Isotopes and samples analyses. Sodium acetate-1- 13 C, potassium hexadecanoate-1,2,3,4-13 C 4 , and glyceryl tri(hexadecanoate-d 31 ) were purchased from Cambridge Isotope Laboratories (Andover, MA) and from Isotec (Miamisburg, and was served at breakfast and lunch for the meal-feeding regimen and infused duodenally for the continuous-feeding regimen.…”

Section: Methodsmentioning

confidence: 99%

“…Isotopic purity was Ͼ98% for all isotopes, and intravenous isotopes were administered as previously described (2). For all subjects, sodium acetate-1- 13 C was given at a dose of 10 g over a 24-h period starting with dinner the night before the study (Fig. 1).…”

Section: Diabetes Vol 54 September 2005mentioning

confidence: 99%

“…A final potential source of fatty acids flowing to the liver postprandially comes from dietary fatty acid influx, which is mediated by chylomicrons produced by the intestine. Animal studies demonstrated that dietary fatty acids were cleared to the liver in vivo (11,12) and that chronic consumption of higher-fat diets results in elevations in liver fat (13,14). However, this pathway has not been measured directly in humans and may provide a significant route of fatty acids used for hepatic TAG synthesis (15).…”

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confidence: 99%

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Increased Dietary Substrate Delivery Alters Hepatic Fatty Acid Recycling in Healthy Men

2005

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Sources of fatty acids flowing to the liver may be used for triacylglycerol (TAG) synthesis. Our objective was to quantify contributions of nonesterified fatty acids (NEFAs), de novo lipogenesis, and dietary fatty acids to VLDL-TAG in the fed state after meal feeding in healthy subjects (n ‫؍‬ 6). The effect of substrate delivery rate was also determined by comparison with data obtained under a continuous-feeding regimen. A liquid diet was administered by mouth or via feeding tube. Contributions of NEFAs, de novo lipogenesis, and dietary fatty acids to VLDL-TAG were quantified using stable isotopes and gas chromatography-mass spectrometry.

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“…Studies have favored the concept that the accumulation of intra-hepatic lipids precedes the state of insulin resistance, while others have shown that hepatic TGs themselves are not toxic and may in fact protect the liver from lipotoxicity by buffering the accumulation of deleterious fatty acids (5)(6)(7)(8). Such findings suggest that hepatic steatosis is not necessarily associated with insulin resistance (9)(10)(11). In agreement with this concept, an identified population of obese humans can stay free of insulin resistance and are metabolically healthy despite morbid obesity (12).…”

Section: Introductionmentioning

confidence: 99%

The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans

Benhamed¹,

Denechaud²,

Lemoine³

et al. 2012

J. Clin. Invest.

344

317

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Nonalcoholic fatty liver disease (NAFLD) is associated with all features of the metabolic syndrome. Although deposition of excess triglycerides within liver cells, a hallmark of NAFLD, is associated with a loss of insulin sensitivity, it is not clear which cellular abnormality arises first. We have explored this in mice overexpressing carbohydrate responsive element-binding protein (ChREBP). On a standard diet, mice overexpressing ChREBP remained insulin sensitive, despite increased expression of genes involved in lipogenesis/fatty acid esterification and resultant hepatic steatosis (simple fatty liver). Lipidomic analysis revealed that the steatosis was associated with increased accumulation of monounsaturated fatty acids (MUFAs). In primary cultures of mouse hepatocytes, ChREBP overexpression induced expression of stearoyl-CoA desaturase 1 (Scd1), the enzyme responsible for the conversion of saturated fatty acids (SFAs) into MUFAs. SFA impairment of insulin-responsive Akt phosphorylation was therefore rescued by the elevation of Scd1 levels upon ChREBP overexpression, whereas pharmacological or shRNA-mediated reduction of Scd1 activity decreased the beneficial effect of ChREBP on Akt phosphorylation. Importantly, ChREBP-overexpressing mice fed a high-fat diet showed normal insulin levels and improved insulin signaling and glucose tolerance compared with controls, despite having greater hepatic steatosis. Finally, ChREBP expression in liver biopsies from patients with nonalcoholic steatohepatitis was increased when steatosis was greater than 50% and decreased in the presence of severe insulin resistance. Together, these results demonstrate that increased ChREBP can dissociate hepatic steatosis from insulin resistance, with beneficial effects on both glucose and lipid metabolism.

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Preserved direct hepatic insulin action in rats with diet-induced hepatic steatosis

Cited by 40 publications

References 46 publications

Defining high-fat-diet rat models: metabolic and molecular effects of different fat types

Defining high-fat-diet rat models: metabolic and molecular effects of different fat types

Increased Dietary Substrate Delivery Alters Hepatic Fatty Acid Recycling in Healthy Men

The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans

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