Up-regulated day-time orexin-orexin receptor system in human adipose tissue associates with a positive metabolic phenotype

Background: The neuropeptide Orexin (Ox) and receptors (OxR1 and OxR2) participate in body-weight and energy homeostasis regulation along the sleep-wake cycle by central and peripheral mechanisms. Since expression of the orexin system in human adipose tissue is poorly-characterized and was inconsistent with results from rodents, we aimed to determine whether Ox-OxR mRNA from human subcutaneous (SC) and visceral (omental, OM) corresponds with adiposity and metabolic (dys)regulation.

Methods: Associations between Ox–OxR expression in human (n=68) adipose tissue, serum orexin and clinical features.

Results: Ox mRNA expressed in 10% of SC and 18.3% of OM samples. While OxR1 was readily detectable, OxR2 was undetectable. OM-Ox expressers were males, and compared to non-expressers, had improved lipid profile (lower total and LDL-cholesterol (p=0.035 and 0.005, respectively)), while SC-Ox expressers had lower CRP (p=0.028) compared to non-expressers. Ox1R relative expression was higher in SC compared to OM (p=0.014). Among non-obese, obese and obese+T2DM the expression was 4.5±1.2, 1.1±0.3, 0.7±0.1 (p<0.001) in SC, and 1.1±0.3, 0.7±0.1, 0.6±0.2 (p=NS) in OM, respectively. Higher OM-OxR1 associated with lower fasting insulin and HOMA-IR, even when adjusted for BMI. The association between BMI and fasting glucose was attenuated by adjustment to SC or OM OxR1 expression. Serum orexin (n=39) was higher in women (p=0.003), and associated with lower insulin, HOMA-IR, triglycerides and triglycerides/HDL. The associations with triglycerides and triglycerides/HDL remained significant upon BMI adjustment. No diurnal oscillation of Ox/OxR was observed in human adipocytes.

Conclusions: Higher day-time predicted peripheral (serum, adipose tissue) Ox-OxR system tone associates with the improved metabolic profile.