Substrate Utilization by Brown Adipose Tissue: What’s Hot and What’s Not?

Abstract

Our understanding of brown adipose tissue (BAT) function in humans has increased rapidly over the past 10 years. This is predominantly due to the development of powerful non-invasive imaging techniques such as positron emission tomography that can quantify BAT mass and function using metabolic tracers. Activation of BAT during cold-induced thermogenesis is an effective way to dissipate energy to generate heat and requires utilization of multiple energy substrates for optimal function. This has led to interest in the activation of BAT as a potential therapeutic target for type 2 diabetes, dyslipidaemia, and obesity. Here, we provide an overview of the current understanding of BAT substrate utilization in humans and highlight additional mechanisms found in rodents, where BAT more prominently contributes to energy expenditure. During thermogenesis, BAT demonstrates substantially increased glucose uptake which appears to be critical for BAT function. However, glucose is not fully oxidized, with a large proportion converted to lactate. The primary energy substrate for thermogenesis is fatty acids, released from brown adipocyte triglyceride stores. Active BAT also sequesters circulating lipids to sustain optimal thermogenesis. Recent evidence reveals that metabolic intermediates from the tricarboxylic acid cycle and glycolytic pathways also play a critical role in BAT function. Understanding the role of these metabolites in regulating thermogenesis and whole body substrate utilization may elucidate novel strategies for therapeutic BAT activation.

MECHANISMS IN ENDOCRINOLOGY: Human brown adipose tissue as a therapeutic target: warming up or cooling down?

“…2 ). In addition to triglyceride stores, BAT sequesters and utilises several circulating substrates such as glucose, fatty acids and some amino acids during thermogenesis (reviewed in ( 23 )). Therefore, BAT activation may improve other metabolic health parameters such as hyperglycaemia and dyslipidaemia in addition to increasing energy expenditure.…”

A Possible Preventive Role of Physically Active Lifestyle during the SARS-CoV-2 Pandemic; Might Regular Cold-Water Swimming and Exercise Reduce the Symptom Severity of COVID-19?

“…Mitochondrial functions and capacity can also be enhanced by brown adipose tissue, which is metabolically activated by cold exposure [ 43 , 44 ]. Recently, Kovaničová et al [ 45 ] have reported that cold-acclimatized ice-water swimmers respond to cold by non-shivering thermogenesis mediated by higher fat oxidation than controls.…”

The transcriptional co-regulator LDB1 is required for brown adipose function

“…Though LDB1 may regulate Ucp1 to affect cold tolerance, reductions in additional gene targets involved in lipid metabolism and thyroid signaling (e.g., Elovl3 , Dio2 ) likely contribute to the severe cold intolerance phenotype. Substrates like glucose and fatty acids are either oxidized as fuel for thermogenesis or used to replenish intercellular lipid pools [ 34 , 35 ]. Given the importance of metabolites for adipocyte thermogenesis, models affecting substrate uptake and utilization, including an adipose triglyceride lipase (ATGL) knockout model, also result in cold intolerance phenotypes [ 36 ].…”