On the potential role of globins in brown adipose tissue: A novel conceptual model and studies in myoglobin knockout mice

Authors: BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC); WANKHADE, UMESH - Arkansas Children'S Nutrition Research Center (ACNC); ONO-MOORE, KIKUMI - Arkansas Children'S Nutrition Research Center (ACNC); CHINTAPALLI, SREE - Arkansas Children'S Nutrition Research Center (ACNC); FOX, RENEE - Arkansas Children'S Nutrition Research Center (ACNC); RUTKOWSKY, JENNIFER - University Of California, Davis; WILLIS, BRANDON - University Of California, Davis; TOLENTINO, TOOD - University Of California, Davis; LLOYD, K.C. KENT - University Of California, Davis; Ferruzzi, Mario

Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/28/2021
Publication Date: 7/1/2021
Citation: Blackburn, M.L., Wankhade, U.D., Ono-Moore, K.D., Chintapalli, S.V., Fox, R., Rutkowsky, J.M., Willis, B.J., Tolentino, T., Lloyd, K., Adams, S.H. 2021. On the potential role of globins in brown adipose tissue: A novel conceptual model and studies in myoglobin knockout mice. American Journal of Physiology - Endocrinology and Metabolism. 321(1):E47-E62. https://doi.org/10.1152/ajpendo.00662.2020.
DOI: https://doi.org/10.1152/ajpendo.00662.2020

Interpretive Summary: Myoglobin confers the distinct red color to muscle and heart, serving as an oxygen-binding protein especially in oxidative fibers. Less attention has been paid to its role in brown fat, a distinct thermogenic tissue that also expresses myoglobin. In a mouse knockout model lacking myoglobin, brown fat had larger lipid droplet accumulation and lower markers of mitochondrial oxidative metabolism, especially in females. This and gene expression patterns suggest a previously underappreciated role for myoglobin as an oxygen-sensor that serves to regulate metabolic pathways in the cell.

Technical Abstract: Myoglobin (Mb) regulates O2 bioavailability in muscle and heart as partial pressure of O2 (pO2) drops with increased tissue workload. Globin proteins also modulate cellular NO pools, "scavenging" NO at higher pO2 and converting NO2- to NO as pO2 falls. Myoglobin binding of fatty acids may also signal a role in fat metabolism. Interestingly, Mb is expressed in brown adipose tissue (BAT), but its function is unknown. Herein, we present a new conceptual model that proposes links between BAT thermogenic activation, concurrently reduced pO2, and NO pools regulated by deoxy/oxy-globin toggling and xanthine oxidoreductase (XOR). We describe the effect of Mb knockout (Mb-/-) on BAT phenotype (lipid droplets, mitochondrial markers uncoupling protein 1 [UCP1] and cytochrome C oxidase 4 [Cox4], transcriptomics) in male and female mice fed a high fat diet (HFD, 45% of energy, ~13 wk), and examine Mb expression during brown adipocyte differentiation. Interscapular BAT weights did not differ by genotype, but there was a higher prevalence of mid-large sized droplets in Mb-/-. COX4 protein expression was significantly reduced in Mb-/- BAT, and a suite of metabolic/NO/stress/hypoxia transcripts were lower. All of these Mb-/--associated differences were most apparent in females. The new conceptual model, and results derived from Mb-/- mice, suggest a role for Mb in BAT metabolic regulation, in part through sexually dimorphic systems and NO signaling. This possibility requires further validation in light of significant mouse-to-mouse variability of BAT Mb mRNA and protein abundances in wildtype mice and lower expression relative to muscle and heart.