Fig 1.
The conplastic mouse strains B6-mtFVB (Atp8 mutation) and B6-mtAKR (control) received high-fat diet (60% calories from fat) (HFD) or control diet (CD) (10% calories from fat) for up to 18 months months after weaning. Body weight and blood glucose levels were measured monthly. Serum leptin and serum insulin levels were monitored till 18 months in an interval of 3 months.
Fig 2.
Model for diet-induced long-term glucose metabolism.
Blood glucose levels (G) and body weight (BW) are regulated by overall energy balance of the body, which is defined by energy intake (Ein) (a) and -expenditure (Eout) (b). Ein depends on diet and demand for food intake (FI) (c1). FI is negatively regulated by elevated insulin (Is) and leptin (Ls) levels. Eout is determined by BW (d) and increased energy expenditure, via Is and Ls, forming a delayed-negative-feedback loop (c2). When Ein is in excess, BW and fat mass (FM) increase. Increased fat mass induces the secretion of both Is and Ls (e). Is levels are also linearly regulated by G (h). Ls and Is also coregulate each other in a positive-feedback loop manner (f), (g).
Table 1.
Model parameters.
Fig 3.
Time-courses of blood glucose, insulin, leptin and body weight in vivo and simulated.
Blood glucose levels exhibited a characteristic two-peak response irrespective of diet and strain. There was a significant effect of high-fat diet (solid lines) on blood glucose response at early time points (3, 6 months of diet) in both control (B6-mtAKR in blue) and mutated (B6-mtFVB in red) strain, however with age the blood glucose levels adapted in all cases (A). Serum insulin levels were significantly lower in mutated strain under control diet (B6-mtAKR, red dashed line), while high-fat diet administration compensated for this lack of insulin by 6 months of age, which then remained elevated over 12 months of diet (red solid line) (B). Serum leptin levels were also significantly higher for mice fed high-fat diet, which further remained elevated over 12 months of diet (solid lines) (C). Mice fed with a high-fat diet had a pronounced increase in body weight (solid lines) throughout the 12 months of feeding compared to mice fed control diet (dashed lines) (D). Model simulations of respective blood glucose levels (E), serum insulin levels (F), serum leptin levels (G) and body weight (H). Shown are means + SEM from n = 8–12 mice per strain and diet.
Fig 4.
Insulin and leptin strongly regulate the timing of blood glucose peak.
Leptin (k5ml) and insulin (k5mi) mediated control of demand for food-intake via Ein (A2, B2). Blood glucose response to 100-fold change in k5ml and k5mi (dashed lines) compared to default blood glucose response (bold line). Arrow depicts the direction of fold-change increase in k5ml and k5mi (A1, B1,). Timing of the blood glucose peak is equally sensitive to fold change in respective leptin and insulin parameters that determine demand for food intake (A3, B3).
Fig 5.
Leptin- and insulin-mediated negative-feedbacks control the blood glucose response.
Insulin (k7i) and leptin (k7l) mediated negative-feedback regulating energy expenditure via Eout (A2, B2). At the later age, leptin has a stronger impact on the blood glucose dynamics. Arrow depicts the direction of fold-change increase in k7i and k7l (A1, B1,). Amplitude of the blood glucose tail is more strongly affected by leptin-mediated negative-feedback (k7l) compared to insulin-mediated negative-feedback (k7i) (B3, A3). Sufficiently strong negative-feedback (e.g. 50 fold increase in k7l, and k7i) leads to a second rise in blood glucose levels (A1 and B1).
Fig 6.
Redundancy of insulin and leptin pathways allows more effective adaptation of blood glucose response with age.
Redundancy of insulin pathway and leptin pathway was removed by alternately downregulating the insulin and leptin derivatives to zero. The blood glucose levels remained elevated at the later age, indicating compromised adaptation, in all cases for both insulin downregulation (A) and leptin downregulation (B).
Fig 7.
Two-peak blood glucose response.
Prolonged feeding of HFD and CD till 18 months of age confirmed the second minor peak in blood glucose levels between 15 to 21 months (A), which was predicted by the second minor rise in the blood glucose simulations after 15 months. Simulations were performed by 50-fold increasing the insulin- and leptin-mediated delayed-negative-feedback (k7l, k7i) (B). Note that the simulations depict normalized glucose values. Shown are means ±SEM from n = 8–12 mice per diet. *p < 0.05 ANOVA plus Sidak’s post test comparing blood glucose levels from month 12–18.5 months (A).