Abstract
The neuropeptide urocortin 3 (UCN3) has a beneficial effect on metabolic disorders, such as obesity, diabetes, and cardiovascular disease. It has been reported that UCN3 regulates insulin secretion and is dysregulated with increasing severity of obesity and diabetes. However, its function in the adipose tissue is unclear. We investigated the overexpression of UCN3 in 3T3-L1 preadipocytes and differentiated adipocytes and its effects on heat shock response, ER stress, inflammatory markers, and glucose uptake in the presence of stress-inducing concentrations of palmitic acid (PA). UCN3 overexpression significantly downregulated heat shock proteins (HSP60, HSP72 and HSP90) and ER stress response markers (GRP78, PERK, ATF6, and IRE1α) and attenuated inflammation (TNFα) and apoptosis (CHOP). Moreover, enhanced glucose uptake was observed in both preadipocytes and mature adipocytes, which is associated with upregulated phosphorylation of AKT and ERK but reduced p-JNK. Moderate effects of UCN3 overexpression were also observed in the presence of 400 μM of PA, and macrophage conditioned medium dramatically decreased the UCN3 mRNA levels in differentiated 3T3-L1 cells. In conclusion, the beneficial effects of UCN3 in adipocytes are reflected, at least partially, by the improvement in cellular stress response and glucose uptake and attenuation of inflammation and apoptosis.
Highlights
Abbreviations activating transcription factor-6 (ATF6): Activating transcription factor 6 CHOP: C/EBP homologous protein corticotropin-releasing factor (CRF): Corticotropin-releasing factor CRHR: Corticotropin-releasing hormone receptor Extracellular signal-regulated kinase GAPDH (ERK): Extracellular signal-regulated kinase glyceraldehyde 3-phosphate dehydrogenase (GAPDH): Glyceraldehyde 3-phosphate dehydrogenase GRP78: 78-KDa glucose-regulated protein HSP60: Heat shock protein 60 HSP72: Heat shock protein 72 HSP90: Heat shock protein 90 heat shock response (HSR): Heat shock response IL6: Interleukin 6 inositol-requiring enzyme-1α (IRE1α): Inositol-requiring enzyme-1α JNK: C-Jun N-terminal kinase macrophage conditioned medium (MaCM): Macrophage conditioned medium palmitic acid (PA): Palmitic acid protein kinase RNA-like endoplasmic reticulum kinase (PERK): Protein kinase RNA-like endoplasmic reticulum kinase type 2 diabetes (T2D): Type 2 diabetes TNFα: Tumor necrosis factor α UCN: Urocortin urocortin 3 (UCN3): Urocortin 3
Overexpression of UCN3 in the absence of PA significantly downregulated the expression of heat shock proteins, HSP60, HSP72, HSP90, and GRP78, at the mRNA expression levels (p < 0.05) (Fig. 1)
We evaluated the effects of UCN3 overexpression at the protein levels via western blotting
Summary
Abbreviations ATF6: Activating transcription factor 6 CHOP: C/EBP homologous protein CRF: Corticotropin-releasing factor CRHR: Corticotropin-releasing hormone receptor ERK: Extracellular signal-regulated kinase GAPDH: Glyceraldehyde 3-phosphate dehydrogenase GRP78: 78-KDa glucose-regulated protein HSP60: Heat shock protein 60 HSP72: Heat shock protein 72 HSP90: Heat shock protein 90 HSR: Heat shock response IL6: Interleukin 6 IRE1α: Inositol-requiring enzyme-1α JNK: C-Jun N-terminal kinase MaCM: Macrophage conditioned medium PA: Palmitic acid PERK: Protein kinase RNA-like endoplasmic reticulum kinase T2D: Type 2 diabetes TNFα: Tumor necrosis factor α UCN: Urocortin UCN3: Urocortin 3. The CRF family consists of ligands, CRF, CRF-bp, and urocortins (UCN) 1,2,3, with their receptors, CRHR1 and CRHR2 These neuropeptides are expressed in discrete areas of the brain and in the adipose tissue, pancreas, skeletal muscle, and h eart[2,3,4]. UCN3 and CRHR2 are highly expressed in pancreatic β cells, where UCN3 modulates insulin secretion through the regulation of somatostatin s ecretion[4] They are co-expressed in the adipose tissue and a dipocytes[12], suggesting local activity in this tissue. The UCN3 levels in the same subjects in the subcutaneous adipose tissue (SAT) increase with body weight and decrease with T 2D12 These findings indicate the complex and crucial roles of UCN3 as a marker/target for controlling metabolic disease progression. We investigated the status of HSR and ER stress response, glucose uptake, and inflammation
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