Effect of 8 Weeks of Overfeeding on Ectopic Fat Deposition and Insulin Sensitivity: Testing the “Adipose Tissue Expandability” Hypothesis

Abstract

OBJECTIVEThe presence of large subcutaneous adipocytes in obesity has been proposed to be linked with insulin resistance and type 2 diabetes through the “adipose tissue expandability” hypothesis, which holds that large adipocytes have a limited capacity for expansion, forcing lipids to be stored in nonadipose ectopic depots (skeletal muscle, liver), where they interfere with insulin signaling. This hypothesis has, however, been largely formulated by cross-sectional findings and to date has not been prospectively demonstrated in the development of insulin resistance in humans.RESEARCH DESIGN AND METHODSTwenty-nine men (26.8 ± 5.4 years old; BMI 25.5 ± 2.3 kg/m2) were fed 40% more than their baseline requirement for 8 weeks. Before and after overfeeding, insulin sensitivity was determined using a two-step hyperinsulinemic-euglycemic clamp. Intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) were measured by 1H-MRS and abdominal fat by MRI. Subcutaneous abdominal adipose and skeletal muscle tissues were collected to measure adipocyte size and markers of tissue inflammation.RESULTSSubjects gained 7.6 ± 2.1 kg (55% fat) and insulin sensitivity decreased 18% (P < 0.001) after overfeeding. IHL increased 46% from 1.5% to 2.2% (P = 0.002); however, IMCL did not change. There was no association between adipocyte size and ectopic lipid accumulation. Despite similar weight gain, subjects with smaller fat cells at baseline had a greater decrease in insulin sensitivity, which was linked with upregulated skeletal muscle tissue inflammation.CONCLUSIONSIn experimental substantial weight gain, the presence of larger adipocytes did not promote ectopic lipid accumulation. In contrast, smaller fat cells were associated with a worsened metabolic response to overfeeding.

Probiotic supplementation attenuates increases in body mass and fat mass during high‐fat diet in healthy young adults

“…In contrast to a previous report (9), insulin sensitivity was not altered by the high-fat diet or VSL#3 treatment in the present study. Our observation is consistent with some (22,35) but not all (23,(36)(37)(38) previous studies. Nevertheless, the reason(s) for this discrepancy is unclear.…”

The color of fat and its central role in the development and progression of metabolic diseases

“…These results are in agreement with the current hypothesis that the presence of small subcutaneous adipocytes protects against insulin resistance and metabolic diseases. However, the study by Johannsen et al [31] showed opposite results. They studied the effect of 8 weeks of excess energy and lipid intake on adipocyte size and expansion in young healthy men: lean subjects with smaller adipocytes responded with a rapidly and not protective adipocyte remodelling, and despite expansion of subcutaneous fat they developed insulin resistance and released more inflammatory markers while subjects with larger subcutaneous adipocytes had less insulin resistance and visceral fat accumulation, maybe due to reduced expandability of these cells [31].…”

“…However, the study by Johannsen et al [31] showed opposite results. They studied the effect of 8 weeks of excess energy and lipid intake on adipocyte size and expansion in young healthy men: lean subjects with smaller adipocytes responded with a rapidly and not protective adipocyte remodelling, and despite expansion of subcutaneous fat they developed insulin resistance and released more inflammatory markers while subjects with larger subcutaneous adipocytes had less insulin resistance and visceral fat accumulation, maybe due to reduced expandability of these cells [31]. It is likely that other factors are involved, possibly a genetic predisposition to type 2 diabetes or in general to ectopic fat deposition [3], [35], [37], [38].…”

“…For many years the phenotype carrying small subcutaneous adipocytes was considered as lower risk to develop insulin resistance, given that these potentially hyperplastic adipocytes could enlarge by increasing the lipid droplets, thus maintaining a good homeostasis [9]. However, this has been proven to be not always the case [31]. In the presence of excess energy intake (positive energy balance), adipose tissue increases lipid storage.…”

“…The reason is not completely known but the MHOs tend to expand their subcutaneous adipose tissue mass, by increasing the number of adipocytes. Phenotypically, they usually have small size adipocytes [31], [76] compared to obese insulin resistant subjects that have are hypertrophic and hypoxic adipocytes with macrophage infiltration [38], [77], [78] (Figure 2). Conversely, individuals with normal body weight when they have abdominal obesity and/or fatty liver are often characterized by insulin resistance (IR), hyperinsulinemia, hyperglycemia, impaired glucose tolerance (IGT), hypercholesterolemia and hypertriglyceridemia, and were defined as "Metabolically Obese Normal Weight", (MONW) [79].…”