Abstract
Lipid uptake can be facilitated via caveolae, specific plasma membrane invaginations abundantly expressed in adipocytes. The dynamin-related protein EH domain-containing 2 (EHD2) stabilizes caveolae at the cell surface. Here, we have examined the importance of EHD2 for lipid handling using primary adipocytes isolated from EHD2 knockout (Ehd2−/−) C57BL6/N mice. Following high-fat diet (HFD) feeding, we found a clear impairment of epididymal, but not inguinal, adipose tissue expansion in Ehd2−/− compared with Ehd2+/+ (WT) mice. Cell size distribution analysis revealed that Ehd2−/− mice had a lower proportion of small adipocytes, and an accumulation of medium-sized adipocytes in both epididymal and inguinal adipose tissue. Further, PPARγ activity, FABP4 and caveolin-1 expression were decreased in adipocytes isolated from Ehd2−/− mice. Inguinal adipocytes isolated from Ehd2−/− mice displayed reduced lipolysis in response to beta adrenergic receptor agonist, which was associated with reduced phosphorylation of perilipin-1 and hormone sensitive lipase (HSL). This impairment could not be rescued using a cAMP analog, indicating that impaired lipolysis in Ehd2−/− primary adipocytes likely occurs at the level of, or downstream of, protein kinase A (PKA). Altogether, these findings pinpoint the importance of EHD2 for maintained intracellular lipid metabolism, and emphasize differences in mechanisms regulating lipid handling in various adipose-tissue depots.
Highlights
There is a global rise in obesity, and it is estimated that 38% of the population will have overweight by year 2030
Age-matched (~11–12 weeks) Ehd2−/− mice displayed lower body weight (BW), but similar blood glucose and serum insulin levels compared with with Ehd2+/+ (WT) (Figures 1B–D)
We found Ehd2−/− mice to have elevated liver triglyceride levels (p = 0.064; Figures 1E,F), a decreased amount of EPI adipose tissue, an increased amount of inguinal (ING) adipose tissue, and trends toward an increased amount of retroperitoneal (RETRO) adipose tissue compared with WT (Figures 1G–I)
Summary
There is a global rise in obesity, and it is estimated that 38% of the population will have overweight by year 2030. Both hypertrophy and hyperplasia of adipocytes occur, causing adipose tissue expansion (Faust et al, 1978; Li et al, 2016). Adipocyte size predicts development of type 2 diabetes (Weyer et al, 2000; Acosta et al, 2016) and sustained overconsumption of calories leads to an accumulation of hypertrophic adipocytes. Impaired differentiation (Grunberg et al, 2014; Acosta et al, 2016) and a limited ability of adipocytes to expand further (McLaughlin et al, 2007) could contribute to adipose tissue dysfunction. A restricted capacity to increase the subcutaneous adipose tissue is hypothesized to favor expansion of visceral adipose tissue and underlie progression toward metabolic disorders (Wajchenberg, 2000; McLaughlin et al, 2011; Shulman, 2014)
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