Endocrine Abstracts

Background: Dysfunctional endoplasmic reticula (ER) and mitochondria contribute to the pathogenesis of obesity and type 2 diabetes mellitus (T2DM). This may, in part, be facilitated by cross-talk between the two organelles during conditions of nutrient excess such as obesity, however the potential impact of ER stress on mitochondrial function has not been well studied. This study investigated whether induction of ER stress in human adipocytes may contribute to mitochondrial dysfunction.

Methods: Differentiated human adipocytes from a cell line (Chub-S7) and primary abdominal subcutaneous (AbdSc) adipocytes from lean and obese donors were treated with Tunicamycin (Tn) to induce ER stress. Mitochondrial function was assessed via oxygen consumption rate (OCR), mitochondrial membrane potential (MMP), ATP concentration, mitochondrial dynamics and number.

Results: Tunicamycin-induced ER stress increased respiratory capacity in a dose- and time-dependent manner (24 h:23%, (P<0.05); 48 h:68%, (P<0.01); 72 h:136%, (P<0.01)), with a preference for glycolysis after 72 h. Both ATP production and MMP were impaired in a corresponding manner (26%, P<0.001; 32%, P<0.0001 respectively), demonstrating that ER stress contributes to impaired mitochondrial function. Confocal microscopy highlighted that ER stress also resulted in reduced mitochondrial elongation (16%, P<0.05) and cellular area occupied by mitochondria (28%, P<0.05). Additionally, pDrp1, a key fission protein was significantly increased with Tn treatment. AbdSc adipocytes from lean subjects had a similar response to ER stress, with a 21% rise in OCR with Tn treatment (P<0.01), whilst adipocytes from obese subjects had a 33% reduced basal respiration than their lean counterparts (P<0.001), demonstrating an existing significantly impaired respiratory function.

Summary: These data suggest that ER stress induces mitochondrial dysfunction and that this is exacerbated during obesity, contributing to metabolic pathologies such as T2DM. This highlights that therapies targeting ER stress in adipocytes may be beneficial in the treatment of chronic ER stress and mitochondrial dysfunction in metabolic disease.