Short-Term Overfeeding May Induce Peripheral Insulin Resistance Without Altering Subcutaneous Adipose Tissue Macrophages in Humans

Abstract

OBJECTIVEChronic low-grade inflammation is a feature of obesity and is postulated to be causal in the development of insulin resistance and type 2 diabetes. The aim of this study was to assess whether overfeeding induces peripheral insulin resistance in lean and overweight humans, and, if so, whether it is associated with increased systemic and adipose tissue inflammation.RESEARCH DESIGN AND METHODSThirty-six healthy individuals undertook 28 days of overfeeding by +1,250 kcal/day (45% fat). Weight, body composition, insulin sensitivity (hyperinsulinemic-euglycemic clamp), serum and gene expression of inflammation markers, immune cell activation, fat cell size, macrophage and T-cell numbers in abdominal subcutaneous adipose tissue (flow cytometry and immunohistochemistry) were assessed at baseline and after 28 days.RESULTSSubjects gained 2.7 ± 1.6 kg (P < 0.001) and increased fat mass by 1.1 ± 1.6% (P < 0.001). Insulin sensitivity decreased by 11% from 54.6 ± 18.7 to 48.9 ± 15.7 μmol/(kg of FFM)/min (P = 0.01). There was a significant increase in circulating C-reactive protein (P = 0.002) and monocyte chemoattractant protein-1 (P = 0.01), but no change in interleukin-6 and intercellular adhesion molecule-1. There were no changes in fat cell size, the number of adipose tissue macrophages or T-cells, or inflammatory gene expression and no change in circulating immune cell number or expression of their surface activation markers after overfeeding.CONCLUSIONSWeight gain-induced insulin resistance was observed in the absence of a significant inflammatory state, suggesting that inflammation in subcutaneous adipose tissue occurs subsequent to peripheral insulin resistance in humans.

CD14 dim CD16 + and CD14 + CD16 + Monocytes in Obesity and During Weight Loss

“…39 An overfeeding challenge rapidly installed an insulin-resistant state in healthy subjects, despite the fact that no significant change occurred in the total macrophage accumulation in the adipose tissue and that there was no change in the number of circulating cells. 40 Additionally, we found that irrespective of the degree of insulin resistance in morbid obesity, macrophage accumulation in omental adipose tissue was associated with the severity of liver fibroinflammation, a well-known and severe complication of obesity. 38 Although the potential link between adipose tissue macrophages and cardiovascular complications in obesity has not been explored yet, several reports have indicated that there is a link between increases in CD16 ϩ monocyte subsets and the development of cardiovascular events 14 -17 and coronary fibrous cap thickness in patients with unstable angina pectoris.…”

Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding

“…Furthermore, consistent with our hypothesis, we show that an increase in lipid metabolites are associated with defects in tissue insulin action, suggesting that lipotoxicity is a generalised mechanism associated with the induction of insulin resistance in individual tissues of mice. Studies in rodents [7,[19][20][21]23], dogs [24] and humans [25][26][27], have shown that short-term exposure to HFD/overfeeding (3-28 days) results in the rapid development of insulin resistance and glucose intolerance. Often these changes occur with only modest increases in fat mass, highlighting that metabolic defects occur prior to the onset of obesity and do not require extensive periods of fat feeding.…”

Altered Glucose Metabolism in Mouse and Humans Conceived by IVF

“…Blood was collected at 1, 3, 4, 5, 6, 7, 8, and 10 min after glucose infusion. Insulin sensitivity was then measured using a 2-h hyperinsulinemic-euglycemic clamp (80 mU/m 2 /min), as described previously (14).…”