Adipocyte size and function in the epididymal and inguinal fat depots

Sammanfattning: Nearly 60% of the worlds adult population is projected to be overweight or obese by 2030. The prevalence of obesity- related diseases, such as type 2 diabetes (T2D), has increased markedly in the past decades. The adipose tissue plays an important role in disease progression of T2D. Adipocyte insulin sensitivity, adipose tissue’s ability to expand, and accumulation of subcutaneous rather than visceral fat, are all important factors for adipose tissue function and systemic metabolic health.This thesis aims to broaden the understanding of adipose tissue function, focusing on the importance of adipocyte cell-size and differences between visceral and subcutaneous adipocytes. This knowledge may in the future contribute to novel treatments that focus on improving function of specific fat depots.Our first project (Paper I) examines the importance of EHD2, a caveolae-associated protein, and its influence on different fat depots by using knockout (Ehd2-/-) mice. Ehd2-/- mice display impaired expansion of epididymal fat, most likely caused by weakened hyperplastic growth, while the inguinal adipocytes exhibit impaired lipolytic response. The results indicate that EHD2 is required for healthy fat expansion since both impaired lipolysis and reduced hyperplastic growth are associated with dysfunctional adipose tissue.In Paper II, we examine the effect of the anti-diabetic drug, rosiglitazone, on hypertrophic adipocytes, and suggest a new mechanism of action for improving insulin-sensitivity in adipocytes. We propose that remodeling of the extracellular matrix (ECM), results in reduced stress-induced intracellular signaling, reduced filamentous (F)-actin and improved insulin-stimulated glucose uptake. The improvement in glucose uptake from rosiglitazone-treated mice are greater in epididymal adipocytes compared to inguinal, which is also reflected in larger changes in ECM expression, intracellular stress signaling and level of F-actin.The last project (Paper III) examines the plasticity of adipose tissue, focusing on cell-size and actin dynamics during weight gain and weight loss. We examine differences between the inguinal and epididymal depots using temporal resolution and correlate the findings to changes in systemic insulin sensitivity. Our data suggest that there are fat depot-specific differences in cell-size plasticity during weight gain, but not during weight loss. Epididymal adipocytes expand in size early during weight gain (after 4 weeks) while inguinal adipocytes expand at a later timepoint (after 12 weeks). During weight loss, both fat depots display intact plasticity, regarding cell-size, weight, and level of F- actin, for short interventions (4 and 8 weeks) but not following prolonged overfeeding (12 weeks).The inguinal depot, in comparison to the epididymal depot, displays stronger correlation between insulin sensitivity and number of hypertrophic adipocytes, suggesting that hypertrophic inguinal adipocytes may contribute to the progression of insulin resistance in mice.