Myoglobin‐mediated lipid shuttling increases adrenergic activation of brown and white adipocyte metabolism and is as a marker of thermogenic adipocytes in humans

Abstract

Background Recruitment and activation of brown adipose tissue (BAT) results in increased energy expenditure (EE) via thermogenesis and represents an intriguing therapeutic approach to combat obesity and treat associated diseases. Thermogenesis requires an increased and efficient supply of energy substrates and oxygen to the BAT. The hemoprotein myoglobin (MB) is primarily expressed in heart and skeletal muscle fibres, where it facilitates oxygen storage and flux to the mitochondria during exercise. In the last years, further contributions of MB have been assigned to the scavenging of reactive oxygen species (ROS), the regulation of cellular nitric oxide (NO) levels and also lipid binding. There is a substantial expression of MB in BAT, which is induced during brown adipocyte differentiation and BAT activation. This suggests MB as a previously unrecognized player in BAT contributing to thermogenesis. Methods and Results This study analyzed the consequences of MB expression in BAT on mitochondrial function and thermogenesis in vitro and in vivo. Using MB overexpressing, knockdown or knockout adipocytes, we show that expression levels of MB control brown adipocyte mitochondrial respiratory capacity and acute response to adrenergic stimulation, signalling and lipolysis. Overexpression in white adipocytes also increases their metabolic activity. Mutation of lipid interacting residues in MB abolished these beneficial effects of MB. In vivo, whole‐body MB knockout resulted in impaired thermoregulation and cold‐ as well as drug‐induced BAT activation in mice. In humans, MB is differentially expressed in subcutaneous (SC) and visceral (VIS) adipose tissue (AT) depots, differentially regulated by the state of obesity and higher expressed in AT samples that exhibit higher thermogenic potential. Conclusions These data demonstrate for the first time a functional relevance of MBs lipid binding properties and establish MB as an important regulatory element of thermogenic capacity in brown and likely beige adipocytes.

COBL, MKX and MYOC Are Potential Regulators of Brown Adipose Tissue Development Associated with Obesity-Related Metabolic Dysfunction in Children

“…Analyses of gene expression in the AT of mice was performed in John Heiker’s lab according to established protocols [ 60 , 61 , 62 ]. RNA isolation was completed using the RNeasy Lipid Tissue Mini kit (Qiagen).…”

Tissue Perfusion and Diffusion and Cellular Respiration: Transport and Utilization of Oxygen

“…During periods of high energy demand, Mb can react with fatty acids to facilitate the removal of ROS. 128,129 Through these interactions, Mb actively regulates intracellular responses to hypoxia and reoxygenation, acting in tandem with Hb and optimizing O 2 availability to the mitochondria for oxidative respiration.…”

Breathe and burn: Novel roles for myoglobin in thermogenesis

“…Christen et al now show that myoglobin (Mb) contributes to mitochondrial respiration and adrenergic response in thermogenic adipocytes (Figure 1). 2 Mb is a single polypeptide chain of 154 amino acids with an iron ion containing heme group that allows for reversible oxygen binding. For decades, Mb was thought to be exclusively present in cardiac and skeletal muscle, where its main functions were storing oxygen and aiding oxygen diffusion.…”