(P16-029-23) Effects of Long-Term Low-Carbohydrate Diet Consumption on the Progression of Metabolic Syndrome Markers in Mice

Objectives: The proportions of macronutrients in diet influence host metabolism and regulate the development of metabolic diseases. We hypothesized that long-term consumption of a diet substantially low in carbohydrates and very high in fat would impact the initiation and progression of metabolic syndrome and fatty liver disease.

Methods: To test our hypothesis, four weeks old male wild-type mice (n=7-9/group) were fed diets with decreasing amounts of carbohydrate (CHO) for 16 weeks. Diets were (1) HCD, high in CHO and low fat (Kcal%, CHO/fat/protein: 70/11/18) (2) MCD, moderately low in CHO and high fat (42/40/18); or (3) LCD, very low in CHO and very high fat (2/80/18). Body weight and calorie intake were monitored weekly. Blood glucose was quantified 2, 4, 6, and 9 weeks post-feeding in 6-hour fasted mice. An oral glucose tolerance test (OGTT) was performed on week 16. Serum total cholesterol (TC) and triglycerides (TG) were quantified after 2, 4, and 6 weeks of feeding. Liver fat accumulation and functions were examined by H&E-histology and quantification of the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Serum beta-hydroxybutyrate (BHB) was measured to evaluate ketogenesis. 

Results: Energy intake was comparable between HCD and LCD mice throughout the study. However, MCD group consumed more calories (p < 0.05) from week 3. Compared to HCD, both MCD and LCD-fed mice displayed higher body weight. The LCD-fed group exhibited high blood glucose at weeks 2 and 9 vs. HCD. Surprisingly, all animals presented similar blood glucose levels at weeks 4 and 6. Notably, LCD-fed mice, but not HCD or MCD-fed mice, displayed insulin resistance, as evident by OGTT performed at week 16. LCD-fed mice showed early hyperlipidemia with an elevated TC (at weeks 4 and 6; p< 0.05) and TG (at week 6; p< 0.05) vs. HCD. At weeks 12 and 16, MCD and LCD-fed mice displayed elevated ALT (p < 0.05) compared to the HCD group. In accordance, these two groups of mice exhibited extensive hepatic fat accumulation. Relative to HCD, we observed an increasing trend in serum BHB levels in the LCD group, albeit with high variability, measured at week 12 (p=0.089).  

Conclusions: The present study suggests that a diet very low in CHO and high in fat may adversely impact weight and triggers metabolic liver diseases in the long term.

Funding Sources: IUBMB Wood-Whelan Research Fellowship
NIH T32 grant (T32DK120509)