Human adipose tissue is a putative direct target of daytime orexin with favorable metabolic effects: A
Nir Goldstein1,2, Hiroshi Tsuneki3, Nikhil Bhandarkar1
1Department of Clinical Biochemistry and Pharmacology and the National Institute of Biotechnology in the Negev, Ben-Gurion University, Beer-Sheva, Israel.
Objective:
Orexin/hypocretin (Ox) and its receptors (OxR), a neuroendocrine system centrally regulating sleep/wakefulness, were implicated in the regulation of peripheral metabolism. It was hypothesized that human adipose tissue constitutes a direct target of the OxA/OxR system that associates with distinct metabolic profile(s).
Methods:
Serum Ox levels and abdominal subcutaneous and visceral adipose tissue expression of Ox/HCRT, OxR1/HCRTR1, and OxR2/HCRTR2 were measured in n = 81 patients.
Results:
Higher morning circulating Ox levels were associated with improved lipid profile and insulin sensitivity, independently of BMI (β = -0.363, p = 0.018 for BMI-adjusted homeostatic model of insulin resistance). Adipose HCRT mRNA was detectable in <20% of patients. Visceral HCRT expressers were mostly (80%) males and, compared with nonexpressers, had lower total and LDL cholesterol. HCRTR1 was readily detectable, and HCRTR2 was undetectable. HCRTR1 mRNA and OxR1 protein expression were higher in subcutaneous than visceral adipose tissue, and among nonobese patients, patients with obesity, and patients with obesity and T2DM were 3.4 (1.0), 0.7 (0.1), 0.6 (0.1) (AU) (p < 0.001) and 1.0 (0.2), 0.5 (0.1), 0.4 (0.1) (AU) (p = NS), respectively. Higher visceral HCRTR1 expression was associated with lower fasting insulin and homeostatic model of insulin resistance, also after adjusting for BMI. In human adipocytes, HCRTR1 expression did not exhibit significant oscillation.
Conclusions:
Human adipose tissue is a putative direct target of the OxA-OxR1 system, with higher morning input being associated with improved metabolic profile.
Insights
The orexin/hypocretin system influences metabolism. Higher morning orexin levels correlate with better lipid profiles and insulin sensitivity, suggesting adipose tissue is a target.
Area of Science:
- Neuroendocrinology
- Metabolic research
- Adipose tissue biology
Background:
- The orexin/hypocretin (Ox) system regulates sleep-wakefulness and is implicated in peripheral metabolism.
- The role of the Ox system in human adipose tissue and its association with metabolic profiles is not fully understood.
Purpose of the Study:
- To investigate if human adipose tissue is a direct target of the OxA/OxR system.
- To explore the association between Ox system components in adipose tissue and metabolic parameters.
Main Methods:
- Measured serum Ox levels and adipose tissue expression of Ox/HCRT, OxR1/HCRTR1, and OxR2/HCRTR2 in 81 patients.
- Analyzed correlations between Ox system markers and metabolic profiles, including lipid levels and insulin sensitivity.
Main Results:
- Higher morning Ox levels were linked to improved lipid profiles and insulin sensitivity, independent of BMI.
- Orexin/hypocretin (HCRT) mRNA was found in less than 20% of patients; visceral HCRT expressers were predominantly male and had lower cholesterol.
- Orexin receptor 1 (HCRTR1) was widely detected, while orexin receptor 2 (HCRTR2) was undetectable. HCRTR1 expression was higher in subcutaneous than visceral adipose tissue and associated with better insulin resistance markers.
Conclusions:
- Human adipose tissue is a potential direct target of the OxA-OxR1 system.
- Increased morning orexin input is associated with an improved metabolic profile.
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