Lipid-Overloaded Enlarged Adipocytes Provoke Insulin Resistance Independent of Inflammation

Abstract

eIn obesity, adipocyte hypertrophy and proinflammatory responses are closely associated with the development of insulin resistance in adipose tissue. However, it is largely unknown whether adipocyte hypertrophy per se might be sufficient to provoke insulin resistance in obese adipose tissue. Here, we demonstrate that lipid-overloaded hypertrophic adipocytes are insulin resistant independent of adipocyte inflammation. Treatment with saturated or monounsaturated fatty acids resulted in adipocyte hypertrophy, but proinflammatory responses were observed only in adipocytes treated with saturated fatty acids. Regardless of adipocyte inflammation, hypertrophic adipocytes with large and unilocular lipid droplets exhibited impaired insulin-dependent glucose uptake, associated with defects in GLUT4 trafficking to the plasma membrane. Moreover, Toll-like receptor 4 mutant mice (C3H/HeJ) with high-fat-diet-induced obesity were not protected against insulin resistance, although they were resistant to adipose tissue inflammation. Together, our in vitro and in vivo data suggest that adipocyte hypertrophy alone may be crucial in causing insulin resistance in obesity.

A low-carbohydrate survey: Evidence for sustainable metabolic syndrome reversal

“…16,17,18,19,20,21,22,23,24 Obesity is commonly viewed as the cause of metabolic syndrome. However, while obesity is highly correlated with the condition, we (and others) suggest that it is the expansion of adipose stores beyond a person's individual storage capacity, 25,26 driven by and in conjunction with hyperinsulinaemia because of the overconsumption of processed dietary carbohydrates in the setting of a Western diet -so prevalent in modern society -that drives this disease process. 26,27,28 Inflammation, especially the presence of pro-inflammatory macrophages in fat stores, such as the visceral adipose tissue, is another key marker of the developing pathology.…”

“…However, while obesity is highly correlated with the condition, we (and others) suggest that it is the expansion of adipose stores beyond a person's individual storage capacity, 25,26 driven by and in conjunction with hyperinsulinaemia because of the overconsumption of processed dietary carbohydrates in the setting of a Western diet -so prevalent in modern society -that drives this disease process. 26,27,28 Inflammation, especially the presence of pro-inflammatory macrophages in fat stores, such as the visceral adipose tissue, is another key marker of the developing pathology. 25,29 The inflamed adipose tissue appears to lose its ability to properly respond to insulin, resulting in loss of its capacity to protectively buffer fatty acids (including sugars and starches converted to fatty acids via de novo lipogenesis to be 'safely' stored).…”

Obesity is associated with depot-specific alterations in adipocyte DNA methylation and gene expression

“…Of these Ehd2, Kctd15 and Prcp have previously been associated with obesity. 17,18,21 The gene encoding the transcription factor, IRF8, which is necessary for production of IgG2a and mounting a type 1 immune response 32 was hypomethylated and exhibited upregulated expression in obesity. This is in line with the finding that visceral adipose tissue inflammation and insulin resistance is dominated by a type 1 response.…”

“…The Ehd2 gene is involved in trafficking of SLC2A4 to the plasma membrane, a process that is impaired in hypertrophic adipocytes independent of inflammation. 17 In the Kctd15 risk gene, SNPs were found to be associated with BMI (P D 2.6E-07, b D 0.06) 18 and with obesity and obesity-related traits (P < 0.005, odds ratio D 1.54). 19 The upregulated genes include Prcp, previously associated with obesity.…”

Adipose morphology and metabolic disease

“…Together, these data suggest that increased circulating lipid may promote the hypertrophic growth of adipocytes. Accordingly, treatment of 3T3-L1 adipocytes with saturated or monounsaturated NEFAs resulted in adipocyte hypertrophy (Kim et al, 2015). With regard to the uptake of lipid into adipocytes, the first step is often the hydrolysis of TAG from circulating lipoproteins by lipoprotein lipase (LPL).…”