Phenotypic comparison of common mouse strains developing high-fat diet-induced hepatosteatosis

Kahle, Melanie; Horsch, Marion; Fridrich, Barbara; Seelig, Anett; Schultheiß, Jürgen; Leonhardt, Jörn; Irmler, Martin; Beckers, Johannes; Rathkolb, Birgit; Wolf, Eckhard; Franke, Nicole; Gailus‐Durner, Valérie; Fuchs, Helmut; Angelis, Martin Hrabé de; Neschen, Susanne

doi:10.1016/j.molmet.2013.07.009

Cited by 55 publications

(65 citation statements)

References 58 publications

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“…For example, the NC-fed mice in this study weighed on average 41 grams, which is a higher body mass compared to adult C57BL/6J mice in similar studies [33]. This body weight phenotype difference is consistent with recent studies comparing the C57BL/6J and C57BL/6N strains, wherein C57BL/6N mice gained more body weight over time than C57BL/6J mice fed NC diet [37, 38]. Because the C57BL/6N mice in our study gained considerable body weight with chow feeding, the high calorie diets did not have pronounced obesigenic effects.…”

Section: Discussionsupporting

confidence: 89%

Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine

Healy¹,

Chow²,

Byrne³

et al. 2015

Journal of Hepatology

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Background & Aims Mice exposed to the hepatocellular carcinogen diethylnitrosamine at 2 weeks of age have a high risk of developing primary liver tumors later in life. Previous studies have demonstrated that diethylnitrosamine-treated mice have increased tumor burden when fed an obesigenic “Western” diet rich in lard fat and sugar. However, the role of dietary fats versus sugars in the promotion of liver cancer is poorly understood. The aim of this study was to determine how altering dietary fats versus sugars affects tumor burden in the diethylnitrosamine model. Methods C57BL/6N mice were treated with diethylnitrosamine at 2 weeks of age and, from 6 to 32 weeks of age, fed one of five diets that differed in fat and sugar content including normal chow, ketogenic, and Western diets. Results Mice fed sugar-rich diets had the greatest tumor burden irrespective of dietary fat content. In contrast, mice fed a high-fat low-sugar diet had the least tumor burden despite obesity and glucose intolerance. When evaluated as independent variables, tumor burden was positively correlated with hepatic fat accumulation, postprandial insulin, and liver IL-6, and inversely correlated with serum adiponectin. In contrast, tumor burden did not correlate with adiposity, fasting insulin, or glucose intolerance. Furthermore, mice fed high sugar diets had lower liver expression of p21 and cleaved caspase-3 compared to mice fed low sugar diets. Conclusions These data indicate that dietary sugar intake contributes to liver tumor burden independent of excess adiposity or insulin resistance in mice treated with diethylnitrosamine.

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Section: Discussionsupporting

confidence: 89%

Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine

Healy¹,

Chow²,

Byrne³

et al. 2015

Journal of Hepatology

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“…Male mice were used since NAFLD is more common in men [33] and this predominance is recapitulated in mouse models [13,34,35]. The C57Bl/6NCrl substrain was chosen since the B6N substrain has demonstrated higher body weight gains, higher percent body fat, and higher liver triglycerides in response to high fat intake than the B6J substrain [36]. This may be due to the known genetic divergence between B6N and B6J substrains, which can affect metabolic responses [37].…”

Section: Introductionmentioning

confidence: 99%

Calcium Reduces Liver Injury in Mice on a High-Fat Diet: Alterations in Microbial and Bile Acid Profiles

et al. 2016

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A high-fat “Western-style” diet (HFWD) promotes obesity-related conditions including non-alcoholic steatohepatitis (NASH), the histologic manifestation of non-alcoholic fatty liver disease (NAFLD). In addition to high saturated fat and processed carbohydrates, the typical HFWD is deficient in calcium. Calcium-deficiency is an independent risk factor for many conditions associated with the Western-style diet. However, calcium has not been widely evaluated in the context of NAFLD. The goal of the present study was to determine if dietary calcium supplementation could protect mice fed a HFWD from NAFLD, specifically by decreasing non-alcoholic steatohepatitis (NASH) and its down-stream consequences. Male C57BL/6NCrl mice were maintained for 18-months on a HFWD containing dietary calcium at either 0.41 gm/kg feed (unsupplemented) or 5.25 gm/kg feed (supplemented). Although there was no difference in body weight or steatosis, calcium-supplemented mice were protected against downstream consequences of hepatic steatosis, manifested by lower inflammation, less fibrosis, and by lower overall histologic NAFLD activity scores (NAS). Calcium supplementation correlated with distinctly segregating gut fecal and cecal microbial communities as defined by 16S rRNA gene sequence. Further, calcium supplementation also correlated with decreased hepatic concentration of the major conjugated murine primary bile acid, tauro-β-muricholic acid (as well as a decrease in the parent unconjugated bile acid). Thus, calcium was protective against progression of diet-induced hepatic steatosis to NASH and end-stage liver disease, suggesting that calcium supplementation may effectively protect against adverse hepatic consequences of HFWD in cases where overall diet modification cannot be sustained. This protective effect occurred in concert with calcium-mediated gut microbial community shifts and alterations of the hepatic bile acid pool.

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“…12,13 In contrast, obesity and diabetes research are mostly conducted in mice on a C57BL/6 background, which facilitates diet-induced obesity and obesity-associated comorbidities, including glucose intolerance and hepatic steatosis. 13–15 Although nude mice have been backcrossed to a pure C57BL/6 background, their susceptibility to diet-induced obesity and comorbid conditions has not been studied in detail.…”

Section: Introductionmentioning

confidence: 99%

Thermoneutral housing is a critical factor for immune function and diet-induced obesity in C57BL/6 nude mice

et al. 2014

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OBJECTIVES Obesity-related cancers represent public health burdens of the first order. Nevertheless, suitable mouse models to unravel molecular mechanisms linking obesity to human cancer are still not available. One translational model is the immunocompromised Foxn1 (winged-helix/forkead transcription factor) nude mouse transplanted with human tumor xenografts. However, most xenograft studies are conducted in nude mice on an in-bred BALB/c background that entails protection from diet-induced obesity. To overcome such resistance to obesity and its sequelae, we here propose the dual strategy of utilizing Foxn1 nude mice on a C57BL/6 background and housing them at their thermoneutral zone. METHODS C57BL/6 nude and corresponding wild-type mice, housed at 23 or 33 °C, were subjected to either low-fat diet or high-fat diet (HFD). Energy expenditure, locomotor activity, body core temperature, respiratory quotient as well as food and water intake were analyzed using indirect calorimetry. Immune function at different housing temperatures was assessed by using an in vivo cytokine capture assay. RESULTS Our data clearly demonstrate that conventional housing protects C57BL/6 nude mice from HFD-induced obesity, potentially via increased energy expenditure. In contrast, HFD-fed C57BL/6 nude mice housed at thermoneutral conditions develop adiposity, increased hepatic triglyceride accumulation, adipose tissue inflammation and glucose intolerance. Moreover, increased circulating levels of lipopolysaccharide-driven cytokines suggest a greatly enhanced immune response in C57BL/6 nude mice housed at thermoneutrality. CONCLUSION Our data reveals mild cold stress as a major modulator for energy and body weight homeostasis as well as immune function in C57BL/6 nude mice. Adjusting housing temperatures to the thermoneutral zone may ultimately be key to successfully study growth and progression of human tumors in a diet-induced obese environment.

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Phenotypic comparison of common mouse strains developing high-fat diet-induced hepatosteatosis

Cited by 55 publications

References 58 publications

Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine

Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine

Calcium Reduces Liver Injury in Mice on a High-Fat Diet: Alterations in Microbial and Bile Acid Profiles

Thermoneutral housing is a critical factor for immune function and diet-induced obesity in C57BL/6 nude mice

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