DACRA induces profound weight loss, satiety control, and increased mitochondrial respiratory capacity in adipose tissue.

BACKGROUND AND OBJECTIVES: Dual amylin and calcitonin receptor agonists (DACRAs) are therapeutic candidates in the treatment of obesity with beneficial effects on weight loss superior to suppression of food intake. Hence, suggesting effects on energy expenditure by possibly targeting mitochondria in metabolically active tissue. METHODS: Male rats with HFD-induced obesity received a DACRA, KBP-336, every third day for 8 weeks. Upon study end, mitochondrial respiratory capacity (MRC), - enzyme activity, - transcriptional factors, and -content were measured in perirenal (pAT) and inguinal adipose tissue. A pair-fed group was included to examine food intake-independent effects of KBP-336. RESULTS: A vehicle-corrected weight loss (23.4 ± 2.8%) was achieved with KBP-336, which was not observed to the same extent with the food-restricted weight loss (12.4 ± 2.8%) (P < 0.001). Maximal coupled respiration supported by carbohydrate and lipid-linked substrates was increased after KBP-336 treatment independent of food intake in pAT (P < 0.01). Moreover, oligomycin-induced leak respiration and the activity of citrate synthase and ß-hydroxyacetyl-CoA-dehydrogenase were increased with KBP-336 treatment (P < 0.05). These effects occurred without changes in mitochondrial content in pAT. CONCLUSIONS: These findings demonstrate favorable effects of KBP-336 on MRC in adipose tissue, indicating an increased energy expenditure and capacity to utilize fatty acids. Thus, providing more mechanistic insight into the DACRA-induced weight loss.

The P2X7 receptor and pannexin-1 are involved in glucose-induced autocrine regulation in ß-cells.

Extracellular ATP is an important short-range signaling molecule that promotes various physiological responses virtually in all cell types, including pancreatic ß-cells. It is well documented that pancreatic ß-cells release ATP through exocytosis of insulin granules upon glucose stimulation. We hypothesized that glucose might stimulate ATP release through other non-vesicular mechanisms. Several purinergic receptors are found in ß-cells and there is increasing evidence that purinergic signaling regulates ß-cell functions and survival. One of the receptors that may be relevant is the P2X7 receptor, but its detailed role in ß-cell physiology is unclear. In this study we investigated roles of the P2X7 receptor and pannexin-1 in ATP release, intracellular ATP, Ca2+ signals, insulin release and cell proliferation/survival in ß-cells. Results show that glucose induces rapid release of ATP and significant fraction of release involves the P2X7 receptor and pannexin-1, both expressed in INS-1E cells, rat and mouse ß-cells. Furthermore, we provide pharmacological evidence that extracellular ATP, via P2X7 receptor, stimulates Ca2+ transients and cell proliferation in INS-1E cells and insulin secretion in INS-1E cells and rat islets. These data indicate that the P2X7 receptor and pannexin-1 have important functions in ß-cell physiology, and should be considered in understanding and treatment of diabetes.