Background

Obesity-related adipose tissue (AT) inflammation causes insulin and catecholamine resistance. Sympathetic stimulation of AT via β3-adrenoceptor (B3AR) induces lipolysis and glucose uptake. While CL316243 (CL) (B3AR agonist) acutely stimulates lipolysis, activates brown/beige AT (BAT) and improves insulin resistance, it might induce AT inflammation at high doses. We here evaluate the effect of chronic low dose CL treatment on DIO mice metabolism and AT inflammation.

Methods

Twenty 6-week-old male C57BL/6 mice, after 10 weeks of high-fat diet (HFD) were intraperitoneally (IP) injected daily with CL (0.01 mg/kg) or saline for 5 weeks. Body weight and composition, food intake and calculated energy expenditure (CEE) were measured weekly. At weeks 4&5 IP glucose tolerance test (IPGTT), and in vivo lipolysis were consecutively done followed by BAT, and white AT (WAT) collection (inguinal (iWAT), and epididymal (eWAT)).

Results

Treated mice had a significant increase in CEE and no weight gain. IPGTT showed significantly lower fasting insulin and AUC of both insulin and blood glucose. The in-vitro lipolysis study showed a significant increase in free fatty acid and glycerol after acute on chronic CL injection. Real-time quantitative RT-PCR showed a significant increase in UCP1 expression in eWAT only with a non-significant increase in browning markers (TMEM, PCG1α). ZIC1 expression was significantly decreased in iWAT. Consistent with other studies B3R expression was lower in BAT compared to WAT. There was a trend for decreased expression in B3R in iWAT after treatment. Inflammation markers (TNFα, IL1B), macrophage marker (F4/80, CxCl11, Nos2) were similar in both groups.

Conclusions

Chronic low dose B3AR stimulation prevented weight gain, increased energy expenditure and improved glucose tolerance in DIO mice on HFD. Preservation of lipolysis in the background of decreased B3R expression suggests another adrenergic receptor stimulation in AT by CL316343.