Modeling the Effect of High Calorie Diet on the Interplay between Adipose Tissue, Inflammation, and Diabetes

Abstract

Background: Type 2 diabetes (T2D) is a chronic metabolic disease potentially leading to serious widespread tissue damage. Human organism develops T2D when the glucose-insulin control is broken for reasons that are not fully understood but have been demonstrated to be linked to the emergence of a chronic inflammation. Indeed such low-level chronic inflammation affects the pancreatic production of insulin and triggers the development of insulin resistance, eventually leading to an impaired control of the blood glucose concentration. On the contrary, it is well-known that obesity and inflammation are strongly correlated.

Aim: In this study, we investigate in silico the effect of overfeeding on the adipose tissue and the consequent set up of an inflammatory state. We model the emergence of the inflammation as the result of adipose mass increase which, in turn, is a direct consequence of a prolonged excess of high calorie intake.

Results: The model reproduces the fat accumulation due to excessive caloric intake observed in two clinical studies. Moreover, while showing consistent weight gains over long periods of time, it reveals a drift of the macrophage population toward the proinflammatory phenotype, thus confirming its association with fatness.

Figures

Figure 1

The volume of an adipocyte changes with an excess (or defect) of caloric intake. We model the swelling and also the recruitment of new adipocytes as stochastic events whose probabilities, respectively, ps and pa are function of the actual volume as in equation (5) and equation (8) and reach 0 and the maximum value, respectively, for limr⟶ϕc/2vt=vc (Figure 2).

Figure 2

The probability functions ps and pa corresponding to the following values of the parameters k1=4, k2=2, k3=8 · 10−6, k4=2 · 10−5, k5=5, and k6=−1. These are the values estimated by using the data in [24, 25] and used throughout the study.

Figure 3

Simulation agreement with the overfeeding phase of the study of (a) Diaz [24], matching an excess caloric intake E=1506 kcal/day, and (b) Tremblay [25] equating to E=1004 kcal/day. In the first case, we simulate a subject with BMI = 24.06, whereas in the second case, the subject has BMI = 20.38. According to the current classification with respect to the body mass index, both subjects are considered normal.

Figure 4

Simulated body weight gain over a period of five years as a function of different excess calorie intake (kcal/day). The simulated individual is a 35-year-old male with an initial BMI of about 21, i.e., a normal subject.

Figure 5

Number of macrophages in the two differentiation classes M1 and M2 per μL of simulated adipose tissue at different time points of simulations of varying calorie diets. The shift toward the M1 proinflammatory phenotype of the macrophage population is not meaningful at the first year (a) but becomes pronounced from year three onwards (c–e) even for relatively lower values of the excess caloric intake (e). Note that at year five (e) also the number of M2 anti-inflammatory macrophages is increased in high calorie diets E ≥ 1500, indicating the attempt of the immune system to counterbalance the inflammation by empowering anti-inflammatory mechanisms.

Figure 6

Kaplan–Meier curve of inflammation set-ups as a function of excess calories E. The fourth year appears as the tipping point for E ≥ 1500 kcal/day.