mouse-model-metabolic-dysfunction-associated-steatotic-liver-disease

Mouse Model of Metabolic Dysfunction-Associated Steatotic Liver Disease with Fibrosis

Liver fibrosis is the most important predictor of adverse outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD). In pre-clinical ...

City University of New York

The well-absorbed alpha-glucosidase inhibitor, miglitol (BAY m 1099), was included in the diets of hypothalamic-dietary obese diabetic rats to investigate its ability to improve glycemia and thereby reverse glucotoxic effects on islet secretory response.

Miglitol (BAY m 1099) treatment of diabetic hypothalamic-dietary obese rats improves islet response to glucose.

High fat, low carbohydrate diets are popularly advocated for weight loss and improvement in metabolic Syndrome X, a constellation of risk factors for type 2 diabetes mellitus and cardiovascular disease. The effects of an energy-restricted (to prevent weight gain in excess of normal growth) high fat (60% of energy), low carbohydrate (15%) diet were assessed in both lean rats and in rats previously rendered obese through ad libitum consumption of the same high fat diet. In obese rats, restriction of intake failed to improve impaired glucose tolerance, hyperinsulinemia, and hypertriglyceridemia, although it lowered visceral fat mass, liver lipid content and in vitro insulin hypersecretion compared with rats continuing to consume the high fat diet ad libitum. In lean rats, restricted intake of the high fat diet impaired glucose tolerance and increased visceral fat mass and liver lipid content. These findings support the conclusion that, in the absence of weight loss, a high fat, low carbohydrate diet not only may be ineffective in decreasing risk factors for cardiovascular disease and type 2 diabetes but may promote the development of disease in previously lower risk, nonobese individuals.

High dietary fat promotes syndrome X in nonobese rats.

The effects of a very low-carbohydrate (VLC), high-fat (HF) dietary regimen on metabolic syndrome were compared with those of an isocaloric high-carbohydrate (HC), low-fat (LF) regimen in dietary obese rats.

Very low-carbohydrate versus isocaloric high-carbohydrate diet in dietary obese rats.

Longitudinal effects of a very low-carbohydrate (VLC) and a calorie-matched high-carbohydrate (HC) weight reduction diet were compared in dietary obese Sprague-Dawley rats exhibiting impaired glucose tolerance and insulin resistance. Obese rats were divided into weight-matched groups: (i) VLC rats consumed an energy-restricted 5% carbohydrate, 60% fat diet for 8 weeks, (ii) HC rats consumed an isocaloric 60% carbohydrate, 15% fat diet, and (iii) HF rats consumed a high-fat diet ad libitum. HC and VLC rats showed similar reductions in body fat and hepatic lipid at the midpoint of the weight-reduction program, indicating effects due to energy deficit. At the end point, however, HC rats showed greater reductions in total and percent body fat, hepatic lipid and intramuscular lipid than did VLC rats, suggesting that diet composition induced changes in the relative efficiencies of the HC and VLC diets over time. HC rats showed marked improvement in glucose tolerance at the midpoint and end point, whereas VLC rats showed no improvement. Impaired glucose tolerance in VLC rats at the end point was due to insulin resistance and an attenuated insulin secretory response. Glucose tolerance in energy-restricted rats correlated negatively with hepatic and intramuscular lipid levels, but not visceral or total fat mass. These findings demonstrate that adaptations to diet composition eventually enabled HC rats to lose more body fat than VLC rats even though energy intakes were equal, and suggest that the elevated levels of hepatic and intramuscular lipid associated with VLC diets might predispose to insulin resistance and impaired glucose tolerance despite weight loss.

Longitudinal adaptations to very low-carbohydrate weight-reduction diet in obese rats: body composition and glucose tolerance.

Maternal obesity increases fetal adiposity which may adversely affect metabolic health of the offspring. Choline regulates lipid metabolism and thus may influence adiposity. This study investigates the effect of maternal choline supplementation on fetal adiposity in a mouse model of maternal obesity. C57BL/6J mice were fed either a high-fat (HF) diet or a control (NF) diet and received either 25 mM choline supplemented (CS) or control untreated (CO) drinking water for 6 weeks before timed-mating and throughout gestation. At embryonic day 17.5, HF feeding led to higher ( < 0.05) percent total body fat in fetuses from the HFCO group, while the choline supplemented HFCS group did not show significant difference versus the NFCO group. Similarly, HF feeding led to higher ( < 0.05) hepatic triglyceride accumulation in the HFCO but not the HFCS fetuses. mRNA levels of lipogenic genes such as , , and , as well as the transcription factor  that favors lipogenesis were downregulated ( < 0.05) by maternal choline supplementation in the HFCS group, which may serve as a mechanism to reduce fat accumulation in the fetal liver during maternal HF feeding. In summary, maternal choline supplementation improves indices of fetal adiposity in obese dams at late gestation.

Choline Supplementation Normalizes Fetal Adiposity and Reduces Lipogenic Gene Expression in a Mouse Model of Maternal Obesity.

Gestational diabetes mellitus (GDM) is characterized by excessive placental fat and glucose transport, resulting in fetal overgrowth. Earlier we demonstrated that maternal choline supplementation normalizes fetal growth in GDM mice at mid-gestation. In this study, we further assess how choline and its oxidation product betaine influence determinants of placental nutrient transport in GDM mice and human trophoblasts. C57BL/6J mice were fed a high-fat (HF) diet 4 weeks prior to and during pregnancy to induce GDM or fed a control normal fat (NF) diet. The HF mice also received 25 mM choline, 85 mM betaine, or control drinking water. We observed that GDM mice had an expanded placental junctional zone with an increased area of glycogen cells, while the thickness of the placental labyrinth zone was decreased at E17.5 compared to NF control mice ( < 0.05). Choline and betaine supplementation alleviated these morphological changes in GDM placentas. In parallel, both choline and betaine supplementation significantly reduced glucose accretion ( < 0.05) in in vitro assays where the human choriocarcinoma BeWo cells were cultured in high (35.5 mM) or normal (5.5 mM) glucose conditions. Expression of angiogenic genes was minimally altered by choline or betaine supplementation in either model. In conclusion, both choline and betaine modified some but not all determinants of placental transport in response to hyperglycemia in mouse and in vitro human cell line models.

Maternal Choline and Betaine Supplementation Modifies the Placental Response to Hyperglycemia in Mice and Human Trophoblasts.

Very low carbohydrate (VLC) diets are used to promote weight loss and improve insulin resistance (IR) in obesity. Since the high fat content of VLC diets may predispose to hepatic steatosis and hepatic insulin resistance, we investigated the effect of a VLC weight-reduction diet on measures of hepatic and whole body insulin resistance in obese rats.

Very low-carbohydrate, high-fat, weight reduction diet decreases hepatic gene response to glucose in obese rats.

Very low-calorie diets (VLCD) are hypocaloric dietary regimens of approximately 400-800 kcal/day that result in 20-30% reductions in body weight, sometimes in just 12-16 weeks. A body of evidence demonstrates that adherence to VLCD in adults with type 2 diabetes (T2D) can result in marked improvements to glycemic control and even full T2D remission, challenging the convention that T2D is a lifelong disease. Although these data are promising, the majority of VLCD studies have focused on weight loss and not T2D remission as a primary endpoint. Moreover, there is a wide range of VLCD protocols and definitions of T2D remission used across these hypocaloric studies. Together the large degree of heterogeneity in VLCD studies, and how T2D remission is defined, leave many gaps in knowledge to efficacy and durability of VLCD approaches for T2D remission. This narrative review examines findings from a body of data from VLCD studies that specifically sought to investigate T2D remission, and discusses the efficacy of VLCD compared to other hypocaloric approaches, and who is likely to benefit from VLCD approaches for T2D remission.

Article	Year
Miglitol (BAY m 1099) treatment of diabetic hypothalamic-dietary obese rats improves islet response to glucose. Obesity research\| PubMed ID: 10023734	1999
High dietary fat promotes syndrome X in nonobese rats. The Journal of nutrition\| PubMed ID: 12840187	2003
Very low-carbohydrate versus isocaloric high-carbohydrate diet in dietary obese rats. Obesity (Silver Spring, Md.)\| PubMed ID: 16988076	2006
Longitudinal adaptations to very low-carbohydrate weight-reduction diet in obese rats: body composition and glucose tolerance. Obesity (Silver Spring, Md.)\| PubMed ID: 20057366	2010
Choline Supplementation Normalizes Fetal Adiposity and Reduces Lipogenic Gene Expression in a Mouse Model of Maternal Obesity. Nutrients\| PubMed ID: 28820499	2017
Maternal Choline and Betaine Supplementation Modifies the Placental Response to Hyperglycemia in Mice and Human Trophoblasts. Nutrients\| PubMed ID: 30326592	2018
Very low-carbohydrate, high-fat, weight reduction diet decreases hepatic gene response to glucose in obese rats. Nutrition & metabolism\| PubMed ID: 31061673	2018
Remission of Type 2 Diabetes with Very Low-Calorie Diets-A Narrative Review. Nutrients\| PubMed ID: 34207117	2021

Kathleen V. Axen

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