GO:0106106 cold-induced thermogenesis: Genes & Methods

Cold-induced thermogenesis (CIT) is the physiological process by which organisms increase metabolic heat production in response to cold ambient temperatures, thereby defending a stable core body temperature. In mammals, this process is most prominently executed by brown adipose tissue (BAT), a specialized organ that dissipates chemical energy as heat through mitochondrial uncoupling. The Gene Ontology term GO:0106106 captures this entire biological process, encompassing the sensing of cold, the recruitment and activation of thermogenic adipocytes, the mobilization of lipid substrates, and the mitochondrial machinery that converts fuel into heat. Understanding CIT is important because it sits at the intersection of energy balance, adipose biology, and systemic metabolism, with implications for obesity, diabetes, and even tumour suppression. Research over the past two decades has moved CIT from a descriptive physiological phenomenon to a molecularly defined pathway. Studies in mice and humans have shown that cold exposure activates sympathetic nerves innervating BAT, triggering lipolysis and the expression of uncoupling protein 1 (UCP1). More recent work has revealed that CIT is not solely a UCP1-dependent process; parallel control by creatine kinase B (CKB) and phosphocreatine cycling is also required for cold-triggered adipocyte thermogenesis. In addition, neutral-lipase-mediated intracellular lipolysis in brown adipocytes is essential for providing fatty acid substrates during cold stress. These findings have expanded the list of genes and pathways that researchers must consider when studying GO:0106106. From a translational perspective, CIT is attractive because it increases energy expenditure and improves metabolic health. Human studies have quantified cold-induced thermogenesis in controlled conditions and shown that it varies with age, body composition, and cold acclimation. Notably, winter-swimming men display altered brown fat thermoregulation and enhanced CIT, suggesting that repeated cold exposure can remodel thermogenic capacity. In preclinical models, activating BAT-mediated thermogenesis by cold exposure suppresses tumour growth, indicating that CIT has systemic effects beyond temperature control. This article provides a research-grade overview of GO:0106106, covering its definition, core mechanisms, key genes, disease links, and the CRISPR-based methods used to study it.

GO:0106106 cold-induced thermogenesis is defined as the process by which heat is generated by increasing metabolism in response to cold ambient temperatures in order to maintain a stable core body temperature. In practical terms, it is the cold-triggered activation of heat-producing pathways, especially in brown adipose tissue, that couples fuel oxidation to heat dissipation rather than ATP synthesis.

GO:0106106 is important because it defines a fundamental homeostatic process that protects organisms from hypothermia while also influencing whole-body energy balance. In mammals, BAT-mediated cold-induced thermogenesis consumes significant amounts of glucose and lipids, making it a potential target for combating obesity and metabolic disease. The process also intersects with mitochondrial biology, lipid metabolism, and systemic signalling, and its activation has been linked to tumour suppression in mice. For researchers, GO:0106106 provides a structured framework to study how cold signals are transduced into metabolic heat, and to identify genes that can be targeted to modulate energy expenditure.

The following genes and proteins are central to the regulation and execution of GO:0106106 cold-induced thermogenesis, based on published functional studies.

Cold-induced thermogenesis is regulated at multiple levels. Sympathetic nervous system activity, triggered by cold sensation, releases norepinephrine that acts on adrenergic receptors in brown adipose tissue. Intracellular lipolysis, mediated by neutral lipases such as ATGL and HSL, provides fatty acid substrates and is required for thermogenesis. Peroxisome-derived lipids regulate cold-induced mitochondrial fission, which is necessary for efficient heat production. In parallel, CKB-mediated phosphocreatine cycling controls thermogenesis independently of UCP1. Newly identified factors such as Feimin promote cold-induced thermogenesis, adding another layer of regulation. Hormonal signals, including thyroid hormone, leptin, and FGF21, also modulate BAT activity and cold tolerance.

Cold-induced thermogenesis increases energy expenditure by burning glucose and lipids in brown adipose tissue, making it a potential target for obesity and type 2 diabetes. Reduced BAT activity is associated with obesity in humans, and cold exposure studies show that CIT can be recruited to enhance metabolic rate. Enhancing CIT through cold acclimation or pharmacological activation may therefore improve metabolic health.

Activation of brown-fat-mediated thermogenesis by cold exposure suppresses tumour growth in mice, linking GO:0106106 to cancer biology. This effect is thought to result from cold-altered global metabolism, including increased glucose consumption by BAT and reduced glucose availability to tumours. These findings suggest that modulating CIT could have systemic anti-tumour effects, although further research is needed.

Impaired cold-induced thermogenesis leads to reduced cold tolerance and increased risk of hypothermia. Mouse models lacking key thermogenic genes, such as UCP1 or CKB, show defective cold-induced thermogenesis and cannot maintain body temperature under cold stress. Similarly, loss of neutral lipase function in brown adipocytes impairs cold-induced thermogenesis. These models are valuable for studying the physiological consequences of defective CIT.

Cold-induced thermogenesis is commonly assessed by measuring oxygen consumption, carbon dioxide production, and body temperature in response to cold exposure. Indirect calorimetry in mice and humans allows quantification of energy expenditure and substrate utilization. Telemetry or rectal temperature probes can monitor core body temperature during cold challenge.

RNA sequencing of brown adipose tissue after cold exposure reveals global changes in gene expression, including upregulation of UCP1 and other thermogenic genes. Quantitative PCR and Western blotting are used to validate candidate genes and proteins. Single-cell RNA sequencing can resolve heterogeneity among brown adipocytes and other cell types in BAT.

Mitochondrial morphology and lipid droplet dynamics can be visualized by confocal and electron microscopy in brown adipocytes. Fluorescent probes for mitochondrial membrane potential and lipid droplets allow real-time assessment of thermogenic activation. Peroxisome-derived lipids can be tracked using lipidomics and fluorescent lipid analogs.

CRISPR-Cas9 knockout, point mutation, and knock-in models enable causal testing of candidate genes in cold-induced thermogenesis. Pharmacological inhibitors of lipolysis or mitochondrial fission can complement genetic approaches. Adrenergic agonists and cold exposure are used to activate thermogenesis in vitro and in vivo.

Researchers studying cold-induced thermogenesis-related genes often need to determine whether a candidate gene is causally involved in heat production, substrate supply, or mitochondrial remodeling. EDITGENE provides a comprehensive suite of CRISPR-based services to accelerate this discovery process, from knockout to knock-in and library screening.

GO:0106106 cold-induced thermogenesis is a fundamental biological process that couples cold sensation to metabolic heat production, primarily in brown adipose tissue. Research has identified a complex network of genes and pathways, including UCP1, CKB, neutral lipases, and peroxisome-derived lipids, that together ensure robust thermogenesis. The process has broad implications for metabolic disease, cold tolerance, and even cancer, making it a rich area for therapeutic exploration. CRISPR-based models are indispensable for dissecting the causal roles of individual genes in cold-induced thermogenesis. By combining knockout, point mutation, knock-in, and overexpression strategies with metabolic phenotyping and bioinformatics, researchers can systematically map the molecular circuitry of CIT. EDITGENE offers end-to-end services to support these efforts, from custom cell model generation to CRISPR library screening.