GO:0120162 positive regulation of cold-induced thermogenesis: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0120162 describes any process that activates or increases the frequency, rate or extent of cold-induced thermogenesis, the regulated production of heat in response to cold exposure.
• In humans, active brown adipose tissue (BAT) is a major determinant of cold-induced energy expenditure, and its presence correlates with distinct circulating metabolite and oxylipin profiles.
• Cold-induced thermogenesis is modulated by endocrine signals including thyroid hormones, with free thyroxine levels associated with the thermogenic response in healthy euthyroid individuals.
• Sympathetic nervous activity and microRNA-33-dependent pathways maintain adaptive thermogenesis, linking neuronal control to beige adipocyte programs.
• Cold exposure also mobilizes short-chain fatty acids and modulates parathyroid and thyroid hormone axes, providing accessible serum markers of BAT metabolism.
• CRISPR-based knockout, knock-in, point-mutation, and overexpression models enable causal testing of candidate regulators of cold-induced thermogenesis in cell and animal systems.
Description
Positive regulation of cold-induced thermogenesis (GO:0120162) is the biological process that activates or increases the frequency, rate, or extent of heat production triggered by cold exposure. This ontology term sits at the intersection of neuroendocrine control, adipose tissue biology, and whole-body energy homeostasis, and it is increasingly studied because of its relevance to metabolic disease and energy balance. In humans, the presence of metabolically active brown adipose tissue determines cold-induced energy expenditure and is reflected in circulating oxylipin and short-chain fatty acid profiles, making this process measurable in vivo. The term is therefore of interest to researchers in metabolism, endocrinology, and neuroscience who seek to understand how cold signals are sensed, integrated, and translated into thermogenic output. Because cold-induced thermogenesis is a regulated, multi-organ process, its positive regulation involves sympathetic outflow, thyroid and parathyroid hormone signaling, adipocyte beigeing, and substrate oxidation. Experimental models that manipulate candidate regulators, including CRISPR-engineered cell and animal models, are essential for establishing causality within this pathway.
positive regulation of cold-induced thermogenesis At A Glance
| GO ID | GO:0120162 |
|---|---|
| GO term | positive regulation of cold-induced thermogenesis |
| Ontology | biological_process |
| Synonym | positive regulation of CIT |
| Definition | Any process that activates or increases the frequency, rate or extent of cold-induced thermogenesis. |
| Major function | Upregulation of heat production in response to cold exposure, integrating neural and endocrine signals. |
| Related process | Adaptive thermogenesis, brown and beige adipocyte activation, sympathetic nervous system control. |
| Key tissues | Brown adipose tissue, skeletal muscle, and central thermoregulatory circuits. |
| Human relevance | Active BAT determines cold-induced energy expenditure and correlates with circulating metabolic markers. |
What Is GO:0120162?
In our own words, GO:0120162 refers to any molecular or cellular process that enhances, initiates, or sustains the heat-generating response to cold. It does not describe the thermogenic effector machinery itself, but rather the upstream and parallel signals that increase the magnitude or duration of cold-induced thermogenesis. This includes neural, endocrine, and local adipose signals that raise the rate of uncoupled respiration and heat production in thermogenic tissues.
Why Is positive regulation of cold-induced thermogenesis Important in Cell Biology?
Understanding positive regulation of cold-induced thermogenesis is important because this process directly influences whole-body energy expenditure and metabolic health. In humans, the presence of active brown adipose tissue is a determinant of cold-induced energy expenditure and is associated with specific oxylipin and short-chain fatty acid signatures, suggesting that thermogenic capacity can be assessed through circulating biomarkers. Endocrine factors such as free thyroxine are associated with the cold-induced thermogenic response in healthy euthyroid individuals, highlighting the integration of thyroid status with thermoregulation. Moreover, sympathetic nerve activity and microRNA-33-dependent pathways maintain adaptive thermogenesis, linking neuronal and post-transcriptional control to beige adipogenesis. Because cold acclimatization modulates parathyroid and thyroid hormones distinctly, the positive regulation of this process has implications for understanding human adaptation to cold environments. Consequently, this GO term is a focal point for research into obesity, metabolic syndrome, and therapeutic strategies that aim to enhance energy expenditure.
• Active brown adipose tissue determines cold-induced energy expenditure in humans, making this process a measurable physiological trait.
• Circulating short-chain fatty acids act as markers of brown adipose tissue metabolism during cold exposure.
• Free thyroxine levels are associated with cold-induced thermogenesis in healthy euthyroid individuals, linking thyroid status to thermoregulation.
• Sympathetic nerve activity and microRNA-33 maintain adaptive thermogenesis, connecting neuronal control to beige adipocyte biology.
• Cold exposure distinctively modulates parathyroid and thyroid hormones in cold-acclimatized versus non-acclimatized humans.
• Preoptic pathways provide parallel neural circuits for thermoregulation, offering a neuroanatomical basis for positive regulation.
• Single-nucleus RNA sequencing has defined adipose tissue subpopulations contributing to cold adaptation in Tibetan pigs.
• A novel cAMP signaling mediator is involved in beige adipogenesis, expanding the molecular toolkit for thermogenesis regulation.
• The process is a potential therapeutic target for increasing energy expenditure in metabolic disease.
• CRISPR-based models allow causal testing of candidate regulators within this pathway.
What Happens During positive regulation of cold-induced thermogenesis?
Cold sensing and central integration
In simple terms: The brain detects cold and sends signals to turn up heat production.
Cold exposure is sensed by peripheral thermoreceptors and integrated in the central nervous system. Parallel preoptic pathways have been shown to mediate thermoregulatory responses, providing a neural substrate for the positive regulation of cold-induced thermogenesis. These central circuits coordinate sympathetic outflow to thermogenic tissues, thereby initiating the thermogenic response.
Sympathetic activation and microRNA control
In simple terms: Nerve signals and small RNA molecules boost the thermogenic program.
Sympathetic nerve activity is a key positive regulator of adaptive thermogenesis. microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity, demonstrating that post-transcriptional regulators can amplify the thermogenic response. This level of control ensures that thermogenesis is matched to environmental demand.
Endocrine modulation by thyroid and parathyroid hormones
In simple terms: Hormones fine-tune how much heat the body makes in the cold.
Thyroid hormones are established modulators of thermogenesis. Free thyroxine levels are associated with cold-induced thermogenesis in healthy euthyroid individuals. In addition, cold exposure distinctively modulates parathyroid and thyroid hormones in cold-acclimatized and non-acclimatized humans, indicating that endocrine axes contribute to the positive regulation of this process.
Beige adipogenesis and cAMP signaling
In simple terms: Certain fat cells become heat-producing cells through a cAMP-driven program.
The recruitment of beige adipocytes increases thermogenic capacity. A novel cAMP signaling mediator has been implicated in beige adipogenesis, linking cyclic AMP signaling to the positive regulation of cold-induced thermogenesis. This pathway promotes the appearance of thermogenic adipocytes within white adipose depots.
Metabolic and circulating markers of BAT activity
In simple terms: Blood molecules can reveal how active brown fat is.
Cold-induced serum short-chain fatty acids act as markers of brown adipose tissue metabolism in humans. Similarly, the presence of active brown adipose tissue determines cold-induced energy expenditure and oxylipin profiles. These circulating signatures provide accessible readouts of the positive regulation of thermogenesis.
Adipose tissue subpopulations in cold adaptation
In simple terms: Different types of fat cells work together to adapt to cold.
Single-nucleus RNA sequencing has defined adipose tissue subpopulations that contribute to cold adaptation in Tibetan pigs, revealing cellular heterogeneity in the thermogenic response. Such studies identify specific cell states that may be positively regulated during cold acclimation.
Key Genes Involved in GO:0120162 positive regulation of cold-induced thermogenesis
The following genes and proteins have been implicated in the positive regulation of cold-induced thermogenesis based on the cited literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| UCP1 | Uncoupling protein 1, thermogenic effector in brown adipocytes | Marker of BAT activity; target for thermogenesis studies |
| DIO2 | Type 2 deiodinase, converts T4 to active T3 in thermogenic tissues | Links thyroid hormone signaling to cold-induced thermogenesis |
| THRA | Thyroid hormone receptor alpha | Mediates thyroid hormone effects on thermogenesis |
| THRB | Thyroid hormone receptor beta | Mediates thyroid hormone effects on thermogenesis |
| ADRB3 | Beta-3 adrenergic receptor | Mediates sympathetic stimulation of thermogenesis |
| MIR33 | microRNA-33 | Maintains adaptive thermogenesis via sympathetic nerve activity |
| PRDM16 | Transcriptional co-regulator of brown/beige adipogenesis | Controls thermogenic gene programs |
| PGC1A (PPARGC1A) | Transcriptional coactivator of mitochondrial biogenesis | Supports oxidative metabolism in thermogenic adipocytes |
| CREB1 | cAMP-responsive transcription factor | Mediates cAMP signaling in beige adipogenesis |
| PTH | Parathyroid hormone | Modulated by cold exposure; endocrine regulator |
| TSH | Thyroid-stimulating hormone | Modulated by cold exposure; endocrine regulator |
| T4/T3 | Thyroid hormones | Associated with cold-induced thermogenesis |
| SCFA | Short-chain fatty acids | Circulating markers of BAT metabolism |
| Oxylipins | Lipid mediators | Correlate with active BAT and energy expenditure |
| Preoptic neurons | Central thermoregulatory neurons | Mediate parallel thermoregulatory pathways |
| Adipose subpopulations | Heterogeneous adipose cell states | Contribute to cold adaptation |
How Is positive regulation of cold-induced thermogenesis Regulated?
The positive regulation of cold-induced thermogenesis is controlled at multiple levels. Centrally, preoptic pathways integrate thermal information and drive sympathetic outflow. Peripherally, sympathetic nerve activity is modulated by microRNA-33, which maintains adaptive thermogenesis. Endocrine regulation involves thyroid hormones, with free thyroxine associated with the thermogenic response, and cold exposure distinctively modulates parathyroid and thyroid hormones in acclimatized and non-acclimatized individuals. At the cellular level, cAMP signaling mediators promote beige adipogenesis, increasing thermogenic capacity. Circulating short-chain fatty acids and oxylipins reflect BAT activity and may serve as feedback or marker molecules.
positive regulation of cold-induced thermogenesis and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| UCP1 | Obesity, impaired thermogenesis | UCP1 knockout brown adipocytes; overexpression in white adipocytes |
| DIO2 | Thyroid hormone-dependent thermogenesis | DIO2 point-mutation knock-in in adipocytes |
| MIR33 | Metabolic syndrome, dysregulated thermogenesis | miR-33 knockout mouse; overexpression in sympathetic neurons |
| ADRB3 | Obesity, reduced sympathetic thermogenesis | ADRB3 knockout mouse; tagged knock-in for imaging |
| PRDM16 | Brown/beige adipocyte dysfunction | PRDM16 knockout and overexpression in adipocyte precursors |
Obesity and metabolic syndrome
Impaired positive regulation of cold-induced thermogenesis may reduce energy expenditure and contribute to obesity. Active brown adipose tissue determines cold-induced energy expenditure in humans, and its presence is associated with distinct oxylipin profiles. Enhancing thermogenesis is therefore a potential strategy for increasing energy expenditure in metabolic disease.
Thyroid disorders
Thyroid hormone status is closely linked to thermogenesis. Free thyroxine levels are associated with cold-induced thermogenesis in healthy euthyroid individuals, and cold exposure modulates parathyroid and thyroid hormones differently in cold-acclimatized versus non-acclimatized humans. These findings suggest that thyroid dysfunction may alter thermoregulatory capacity.
Cold adaptation and environmental physiology
Populations adapted to cold environments, such as Tibetan pigs, show distinct adipose tissue subpopulations contributing to cold adaptation. Understanding these adaptations may inform human cold-related health risks and metabolic resilience.
From positive regulation of cold-induced thermogenesis-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is a candidate gene required for cold-induced thermogenesis? | CRISPR knockout in brown adipocytes or mouse |
| Does a specific point mutation alter thermogenic capacity? | CRISPR point-mutation knock-in in cell lines or mice |
| Does overexpression of a regulator enhance thermogenesis? | CRISPR overexpression (e.g., CRISPRa) in adipocytes |
| Where is a protein localized during cold exposure? | Tagged knock-in with fluorescent or epitope tag |
| Which genes are essential for BAT function? | CRISPR library screening in thermogenic cell models |
| What transcriptional programs change with cold? | RNA-seq and single-nucleus RNA-seq in cold-exposed models |
How to Study the positive regulation of cold-induced thermogenesis Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Indirect calorimetry | Energy expenditure | Cold-induced thermogenesis in humans |
| Lipidomics/mass spectrometry | Oxylipins and short-chain fatty acids | BAT activity markers |
| Single-nucleus RNA-seq | Adipose cell subpopulations | Cold adaptation studies |
| Immunoassay | Thyroid and parathyroid hormones | Endocrine modulation |
| Microneurography | Sympathetic nerve activity | Neural control of thermogenesis |
| CRISPR knockout | Gene function | Causal testing of regulators |
| CRISPR activation | Gene overexpression | Enhancement of thermogenic programs |
| Tagged knock-in | Protein localization | Imaging in thermogenic tissues |
Metabolic phenotyping
Cold-induced energy expenditure and BAT activity can be assessed in humans using indirect calorimetry and imaging, as shown by studies linking active BAT to oxylipin profiles. These methods quantify the physiological output of positive regulation.
Circulating biomarker profiling
Serum short-chain fatty acids and oxylipins serve as markers of BAT metabolism during cold exposure. Mass spectrometry-based lipidomics enables their measurement in human cohorts.
Single-nucleus RNA sequencing
Single-nucleus RNA sequencing defines adipose tissue subpopulations contributing to cold adaptation, as demonstrated in Tibetan pigs. This approach reveals cell-type-specific regulators of thermogenesis.
Hormone and sympathetic activity measurements
Thyroid and parathyroid hormone levels are measured by immunoassay, and sympathetic nerve activity can be assessed via microneurography or catecholamine metabolites. These readouts capture endocrine and neural inputs to thermogenesis.
How CRISPR Can Be Used to Study GO:0120162 positive regulation of cold-induced thermogenesis
Knockout
CRISPR knockout of candidate genes in brown adipocytes or mouse models can determine whether a gene is required for cold-induced thermogenesis. For example, knocking out UCP1 or ADRB3 would test their necessity in the thermogenic response.
Point Mutation
Point-mutation knock-in can model human variants in genes such as DIO2 or THRA to assess their impact on thyroid hormone signaling and thermogenesis. This approach links specific alleles to thermogenic capacity.
Knock-in
Tagged knock-in of thermogenic regulators enables visualization and interaction studies in native tissues. For instance, tagging PRDM16 or PGC1A allows tracking of their localization during cold exposure.
Overexpression
CRISPR activation or transgenic overexpression of regulators such as microRNA-33 or cAMP signaling mediators can enhance adaptive thermogenesis, providing gain-of-function evidence.
How EDITGENE Supports positive regulation of cold-induced thermogenesis Research
Researchers studying positive regulation of cold-induced thermogenesis-related genes often need to determine whether a candidate gene is causally involved in thermogenic responses or merely correlated with them. EDITGENE provides a comprehensive suite of CRISPR-based services to enable such causal experiments in relevant cell and animal models.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of cold-induced thermogenesis research.
Frequently Asked Questions About positive regulation of cold-induced thermogenesis
What is GO:0120162?
GO:0120162 is the Gene Ontology term for positive regulation of cold-induced thermogenesis, describing any process that activates or increases the frequency, rate, or extent of cold-induced thermogenesis.
What is positive regulation of cold-induced thermogenesis?
It is the biological process that enhances the heat-generating response to cold, involving neural, endocrine, and adipose signals.
What genes are involved in positive regulation of cold-induced thermogenesis?
Key genes include UCP1, DIO2, THRA, THRB, ADRB3, MIR33, PRDM16, and PGC1A, among others.
How is cold-induced thermogenesis measured in humans?
It can be measured by indirect calorimetry, imaging of brown adipose tissue, and circulating markers such as short-chain fatty acids and oxylipins.
What role does brown adipose tissue play in cold-induced thermogenesis?
Active brown adipose tissue determines cold-induced energy expenditure and is associated with specific oxylipin profiles.
How do thyroid hormones affect cold-induced thermogenesis?
Free thyroxine levels are associated with cold-induced thermogenesis in healthy euthyroid individuals, and cold exposure modulates thyroid and parathyroid hormones.
What is the role of microRNA-33 in thermogenesis?
microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity.
Can CRISPR be used to study cold-induced thermogenesis?
Yes, CRISPR knockout, knock-in, point mutation, and overexpression models enable causal testing of candidate regulators in thermogenic cells and animals.
What are the best cell models for studying cold-induced thermogenesis?
Brown and beige adipocyte cell lines, as well as primary adipocytes, are commonly used; single-nucleus RNA-seq has identified relevant subpopulations.
What diseases are linked to impaired cold-induced thermogenesis?
Obesity, metabolic syndrome, and thyroid disorders are linked to altered thermogenic capacity.
Conclusion
GO:0120162 positive regulation of cold-induced thermogenesis is a central biological process that integrates neural, endocrine, and adipose signals to enhance heat production in response to cold. Human studies have demonstrated that active brown adipose tissue, thyroid hormones, and circulating metabolites such as short-chain fatty acids and oxylipins are key correlates of this process. Mechanistic insights from microRNA-33 and cAMP signaling pathways further highlight the molecular complexity of thermogenic regulation. Continued research using CRISPR-based models will be essential to establish causality and to identify therapeutic targets for metabolic disease.
References
- 1. Monfort-Pires M et al.. 2026. Cold-Induced Serum Short-Chain Fatty Acids Act as Markers of Brown Adipose Tissue Metabolism in Humans.. J Clin Endocrinol Metab 111(5):1377-1388 PMID: 41206219
- 2. Maushart CI et al.. 2021. Free Thyroxine Levels are Associated with Cold Induced Thermogenesis in Healthy Euthyroid Individuals.. Front Endocrinol (Lausanne) 12:666595 PMID: 34194392
- 3. Kulterer OC et al.. 2020. The Presence of Active Brown Adipose Tissue Determines Cold-Induced Energy Expenditure and Oxylipin Profiles in Humans.. J Clin Endocrinol Metab 105(7) PMID: 32343312
- 4. Kim JS et al.. 2023. Involvement of a novel cAMP signaling mediator for beige adipogenesis.. Metabolism 143:155536 PMID: 36933791
- 5. Yoshida K et al.. 2009. Parallel preoptic pathways for thermoregulation.. J Neurosci 29(38):11954-64 PMID: 19776281
- 6. Horie T et al.. 2021. microRNA-33 maintains adaptive thermogenesis via enhanced sympathetic nerve activity.. Nat Commun 12(1):843 PMID: 33594062
- 7. Liu J et al.. 2025. Single-nucleus RNA sequencing defines adipose tissue subpopulations that contribute to Tibetan pig cold adaptation.. BMC Biol 23(1):107 PMID: 40275312
- 8. Kovaničová Z et al.. 2020. Cold Exposure Distinctively Modulates Parathyroid and Thyroid Hormones in Cold-Acclimatized and Non-Acclimatized Humans.. Endocrinology 161(7) PMID: 32242612
