Hypertrophy and/or Hyperplasia: Dynamics of Adipose Tissue Growth

Abstract

Adipose tissue grows by two mechanisms: hyperplasia (cell number increase) and hypertrophy (cell size increase). Genetics and diet affect the relative contributions of these two mechanisms to the growth of adipose tissue in obesity. In this study, the size distributions of epididymal adipose cells from two mouse strains, obesity-resistant FVB/N and obesity-prone C57BL/6, were measured after 2, 4, and 12 weeks under regular and high-fat feeding conditions. The total cell number in the epididymal fat pad was estimated from the fat pad mass and the normalized cell-size distribution. The cell number and volume-weighted mean cell size increase as a function of fat pad mass. To address adipose tissue growth precisely, we developed a mathematical model describing the evolution of the adipose cell-size distributions as a function of the increasing fat pad mass, instead of the increasing chronological time. Our model describes the recruitment of new adipose cells and their subsequent development in different strains, and with different diet regimens, with common mechanisms, but with diet- and genetics-dependent model parameters. Compared to the FVB/N strain, the C57BL/6 strain has greater recruitment of small adipose cells. Hyperplasia is enhanced by high-fat diet in a strain-dependent way, suggesting a synergistic interaction between genetics and diet. Moreover, high-fat feeding increases the rate of adipose cell size growth, independent of strain, reflecting the increase in calories requiring storage. Additionally, high-fat diet leads to a dramatic spreading of the size distribution of adipose cells in both strains; this implies an increase in size fluctuations of adipose cells through lipid turnover.

Figure 1. Changes in body composition of FVB and C57 mice under standard chow (REG) and high-fat (HF) conditions.

(A) Body weight. (B) Fat mass. Body composition was measured at indicated time points in 8 mice per group using Echo 3-in-1 MRI analyzer. High-fat and control feeding were initiated at the age of 5 weeks. X-axis indicates weeks of controlled feeding. One of three independent experiments is shown. Values given are mean±SEM.

Figure 2. Physiological characteristics of FVB and C57 mice.

(A) Glucose tolerance test was performed on week 10 of controlled feeding with chow and high-fat diet. Mice were fasted overnight and injected with glucose (2 mg/g, i.p.). Each group was represented by 8 mice. (B) Whole body oxidation of oleic acid was measured 10-week old male FVB ad C57 mice in non-fasted state (8 mice per group) as described in Gautam et al. . (C) Oxidation in palmitic acids was measured in soleus muscle dissected from 10-week-old FVB and C57 mice maintained on chow diet (8 mice per group). Samples were collected at 8 am from randomly fed mice or mice fasted for 18 hours [methods in Toyoshima et al. [46]]. (D) Triglyceride clearance in FVB and C57 male mice after 11 weeks of controlled feeding with chow and high fat diet. Mice were fasted for 4 h and then given 400 µl of peanut oil by a gavage. Plasma was collected hourly for 5 h from the tail vein for triglyceride measurement. Each group was represented by 8 mice.

Figure 3. Normalized cell-size distribution in epididymal fat pad.

One typical example of five-week-old control FVB mice is plotted. Circles indicate measured data points, while the line represents a fitting curve that is the sum of one Gaussian and two exponential functions.

Figure 4. Size and number increase of epididymal fat cells with respect to epididymal fat pad mass.

(A) and (B): the correlation between epididymal fat pad mass and volume-weighted mean cell size is fitted with a power law with (A) and (B) , which is plotted with solid lines. (C) and (D): the correlation between epididymal fat pad mass and total cell number is fitted into an exponential function with initial fat pad mass , initial cell number , and cell-number increasing rate , plotted with dashed lines (chow diet) and solid lines (high-fat diet). Fitted parameter values are summarized in Table 2.

Figure 5. Changes of cell-size distributions with the mass increase of epididymal fat pad under chow and high-fat diets.

Initial cell-size distributions of five-week-old control mice are given at the first row of each column with dashed lines. Dots show experimental results. Note that the results are ordered with epididymal fat pad mass, not with the chronological time (weeks of controlled feeding) shown in parentheses. Solid lines represent the normalized cell-size distributions corresponding to the given epididymal fat pad mass, predicted by the adipose tissue growth model.

Figure 6. Size-dependent growth rate for the increment of epididymal fat pad mass.

Here the mean parameter values in Table 2 are used for this plot. Symbols are shown to aid comparison between lines.