GO:0120161 regulation of cold-induced thermogenesis: Biological Process, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0120161 (regulation of cold-induced thermogenesis) is a biological process that modulates the frequency, rate or extent of cold-induced thermogenesis, the physiological heat production triggered by cold exposure.
• Cold-induced thermogenesis is primarily executed by brown adipose tissue (BAT) and beige adipocytes, which dissipate energy as heat through mitochondrial uncoupling.
• Key regulatory nodes include peroxisome-derived lipids that drive cold-induced mitochondrial fission, the RNA-binding protein FAM195A, CLSTN3β for adipocyte multilocularity, and HIF2α-mediated ceramide catabolism.
• Additional regulators include ChREBP-mediated up-regulation of Them1 and a truncated adenylyl cyclase 3 that acts as a rheostat of brown fat function.
• Dysregulation of cold-induced thermogenesis contributes to obesity, insulin resistance, and metabolic disorders, making it a therapeutic target.
• CRISPR-based knockout, knock-in, and overexpression models are essential to dissect causal roles of candidate regulators in thermogenesis [1,2,3,4,6,7].
Description
Regulation of cold-induced thermogenesis (GO:0120161) is a biological process that modulates the frequency, rate or extent of cold-induced thermogenesis, the physiological response that increases heat production in response to cold exposure. This process is critical for maintaining body temperature and energy balance in mammals, and its dysregulation is linked to metabolic diseases such as obesity and type 2 diabetes. Cold-induced thermogenesis primarily occurs in brown adipose tissue (BAT) and beige adipocytes, where uncoupling protein 1 (UCP1) dissipates the proton gradient across the inner mitochondrial membrane to generate heat. The regulation of this process involves a complex network of transcriptional, post-transcriptional, and metabolic factors that sense cold and adjust thermogenic output accordingly [1,2,3,4,6,7]. Understanding these regulatory mechanisms is essential for developing therapeutic strategies to enhance energy expenditure and combat metabolic disorders. This article synthesizes current knowledge on the regulation of cold-induced thermogenesis, highlighting key genes, molecular mechanisms, and research methodologies, with a focus on CRISPR-based approaches for functional validation.
regulation of cold-induced thermogenesis At A Glance
| GO ID | GO:0120161 |
|---|---|
| GO term | regulation of cold-induced thermogenesis |
| Ontology | biological_process |
| Synonym | regulation of CIT |
| Definition | Any process that modulates the frequency, rate or extent of cold-induced thermogenesis. |
| Major function | Modulates heat production in response to cold, primarily in brown and beige adipose tissue. |
| Related processes | Mitochondrial fission, lipid catabolism, adipocyte differentiation, thermogenesis. |
| Key tissues | Brown adipose tissue (BAT), beige adipocytes, skeletal muscle. |
| Physiological outcome | Maintenance of body temperature and energy homeostasis. |
What Is GO:0120161?
GO:0120161, regulation of cold-induced thermogenesis, is defined as any process that modulates the frequency, rate or extent of cold-induced thermogenesis. In other words, it encompasses all molecular and cellular events that control how much heat is produced in response to cold, rather than the heat production itself. This regulation can occur at multiple levels, including gene expression, protein activity, mitochondrial dynamics, and lipid metabolism [1,2,3,4,6,7].
Why Is regulation of cold-induced thermogenesis Important in Cell Biology?
Regulation of cold-induced thermogenesis is vital for survival in cold environments and for whole-body energy balance. In humans, cold-induced thermogenesis contributes to daily energy expenditure and is inversely correlated with obesity. Brown adipose tissue activity, a major component of cold-induced thermogenesis, is reduced in obese and diabetic individuals, and its reactivation improves metabolic health in animal models. Therefore, understanding the regulatory mechanisms of cold-induced thermogenesis offers promising avenues for treating obesity and related metabolic disorders.
• Maintains core body temperature during cold exposure.
• Increases energy expenditure by burning calories as heat.
• Dysregulation leads to obesity and insulin resistance.
• Brown adipose tissue activity is inversely associated with body mass index in humans.
• Provides a target for anti-obesity therapies.
• Involves mitochondrial dynamics and lipid signaling.
• Regulated by RNA-binding proteins and transcriptional factors [2,6].
• Modulated by adipocyte-derived factors like CLSTN3β.
• Linked to ceramide catabolism and atherosclerosis suppression.
• Affected by stress hormones via ChREBP and Them1.
What Happens During regulation of cold-induced thermogenesis?
Cold Sensing and Signal Transduction
In simple terms: When you get cold, your body senses it and sends signals to fat cells to start producing heat.
Cold exposure activates thermoreceptors and sympathetic nervous system outflow, leading to norepinephrine release in brown adipose tissue (BAT). This triggers cAMP signaling and activation of protein kinase A (PKA), which phosphorylates downstream targets to initiate thermogenesis. The truncated adenylyl cyclase 3 (AC3) acts as a rheostat to modulate cAMP levels and brown fat function.
Mitochondrial Dynamics and Peroxisome-Derived Lipids
In simple terms: Fat cells need to reshape their energy factories (mitochondria) to burn calories efficiently.
Peroxisome-derived lipids are essential for cold-induced mitochondrial fission in adipocytes, a process required for efficient thermogenesis. Knockout of peroxisomal genes impairs mitochondrial fission and reduces cold tolerance. This highlights the role of lipid signaling in regulating thermogenesis.
Adipocyte Multilocularity and Lipid Utilization
In simple terms: Fat cells become packed with many small fat droplets to quickly access energy for heat production.
CLSTN3β enforces adipocyte multilocularity, a hallmark of thermogenic adipocytes, by promoting lipid droplet fragmentation and utilization. Loss of CLSTN3β leads to unilocular lipid droplets and impaired thermogenesis.
Transcriptional and Post-Transcriptional Control
In simple terms: Genes that control heat production can be turned on or off by special proteins.
The RNA-binding protein FAM195A regulates cold-induced thermogenesis by modulating mRNA stability and translation of thermogenic genes. ChREBP up-regulates Them1 in response to chronic stress, coordinating thermogenesis with glycolysis and lipogenesis. These factors fine-tune the thermogenic program.
Ceramide Catabolism and Metabolic Crosstalk
In simple terms: Breaking down certain fats can help reduce inflammation and protect against heart disease.
Adipocyte hypoxia-inducible factor 2α (HIF2α) promotes ceramide catabolism, which suppresses atherosclerosis and supports thermogenesis. This links cold-induced thermogenesis regulation to cardiovascular health.
Key Genes Involved in GO:0120161 regulation of cold-induced thermogenesis
The following genes and proteins are key regulators of cold-induced thermogenesis, as identified in recent literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| UCP1 | Uncoupling protein 1, dissipates proton gradient to generate heat | Central effector of thermogenesis; marker of brown/beige adipocytes |
| FAM195A | RNA-binding protein regulating mRNA stability of thermogenic genes | Post-transcriptional regulator; knockout impairs cold tolerance |
| CLSTN3β | Enforces adipocyte multilocularity and lipid utilization | Required for efficient thermogenesis; knockout leads to unilocular fat |
| HIF2α | Promotes ceramide catabolism and suppresses atherosclerosis | Links thermogenesis to cardiovascular protection |
| ChREBP | Transcription factor up-regulating Them1 under chronic stress | Coordinates thermogenesis with glycolysis and lipogenesis |
| Them1 | Thioesterase superfamily member 1, involved in lipid metabolism | Regulated by ChREBP; modulates thermogenesis |
| AC3 | Adenylyl cyclase 3, produces cAMP; truncated form acts as rheostat | Regulates brown fat function via cAMP signaling |
| Peroxisomal genes (e.g., Pex5) | Peroxisome biogenesis and lipid synthesis | Required for cold-induced mitochondrial fission |
| PPARγ | Master regulator of adipocyte differentiation | Controls thermogenic gene expression |
| PGC-1α | Transcriptional coactivator of mitochondrial biogenesis | Enhances thermogenic capacity |
| PRDM16 | Transcriptional coregulator of brown fat identity | Determines brown adipocyte fate |
| BMP7 | Induces brown adipocyte differentiation | Promotes thermogenic phenotype |
| FGF21 | Hormone that enhances thermogenesis | Secreted factor regulating energy balance |
| Irisin | Exercise-induced myokine that promotes browning | Links physical activity to thermogenesis |
| NRF1 | Transcription factor for mitochondrial biogenesis | Supports thermogenic capacity |
| TFAM | Mitochondrial transcription factor A | Essential for mitochondrial DNA maintenance |
| Cidea | Lipid droplet protein in brown fat | Marker of thermogenic adipocytes |
| Dio2 | Type 2 deiodinase, activates thyroid hormone | Increases thermogenesis in BAT |
How Is regulation of cold-induced thermogenesis Regulated?
Regulation of cold-induced thermogenesis is controlled by multiple signaling pathways. The sympathetic nervous system releases norepinephrine, which activates β-adrenergic receptors and cAMP-PKA signaling. This leads to activation of transcription factors such as CREB and downstream targets like UCP1. The RNA-binding protein FAM195A modulates mRNA stability of thermogenic genes. ChREBP up-regulates Them1 in response to chronic stress, integrating thermogenesis with glucose and lipid metabolism. Truncated AC3 acts as a rheostat to prevent excessive cAMP signaling. Additionally, peroxisome-derived lipids are required for mitochondrial fission during cold exposure.
regulation of cold-induced thermogenesis and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| UCP1 | Obesity, insulin resistance | UCP1 knockout mouse; overexpression in adipocytes |
| FAM195A | Cold intolerance, metabolic dysfunction | FAM195A knockout mouse; RNA-seq after cold exposure |
| CLSTN3β | Lipid droplet abnormalities, thermogenic failure | CLSTN3β knockout mouse; adipocyte-specific overexpression |
| HIF2α | Atherosclerosis, ceramide accumulation | HIF2α knockout mouse; adipocyte-specific deletion |
| ChREBP | Chronic stress-induced metabolic syndrome | ChREBP knockout mouse; Them1 overexpression |
Obesity and Metabolic Syndrome
Impaired cold-induced thermogenesis contributes to reduced energy expenditure and obesity. Brown adipose tissue activity is lower in obese individuals, and enhancing thermogenesis promotes weight loss in animal models. Genetic variants in thermogenic genes are associated with obesity risk.
Type 2 Diabetes and Insulin Resistance
Defective thermogenesis in brown fat is linked to insulin resistance. Activation of BAT improves glucose homeostasis and insulin sensitivity. HIF2α-mediated ceramide catabolism in adipocytes also protects against atherosclerosis, a comorbidity of diabetes.
Cardiovascular Disease
Adipocyte HIF2α promotes ceramide catabolism, which suppresses atherosclerosis. This suggests that thermogenic regulation in adipose tissue can influence cardiovascular health beyond energy balance.
From regulation of cold-induced thermogenesis-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X regulate cold-induced thermogenesis? | Knockout mouse (constitutive or conditional) [1,2,3,4,6,7] |
| What is the effect of a point mutation in gene X on thermogenesis? | Point-mutation knock-in mouse |
| How does overexpression of gene X affect thermogenesis? | Transgenic overexpression mouse |
| Where is protein X localized during cold exposure? | Tagged knock-in (e.g., GFP) mouse |
| What are the transcriptomic changes upon cold exposure? | RNA-seq of BAT from wild-type and knockout mice |
| Can CRISPR screening identify novel regulators? | In vivo CRISPR library screening in mice |
How to Study the regulation of cold-induced thermogenesis Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global gene expression | Identify thermogenic gene signatures |
| ChIP-seq | Transcription factor binding sites | Map ChREBP targets |
| Lipidomics | Lipid species and ceramides | Assess ceramide catabolism |
| Seahorse respirometry | Oxygen consumption rate | Measure mitochondrial function |
| Confocal microscopy | Mitochondrial morphology | Visualize fission/fusion |
| Western blot | Protein expression and phosphorylation | Validate signaling changes |
| CRISPR screening | Gene function at scale | Discover novel regulators |
| Cold tolerance test | Core body temperature maintenance | Phenotype knockout mice |
RNA Sequencing (RNA-seq)
RNA-seq measures global gene expression changes in brown adipose tissue after cold exposure or genetic perturbation. It identifies differentially expressed genes and pathways involved in thermogenesis regulation.
Chromatin Immunoprecipitation Sequencing (ChIP-seq)
ChIP-seq maps binding sites of transcription factors such as ChREBP or PPARγ on chromatin, revealing direct targets in thermogenic gene programs.
Metabolomics and Lipidomics
Metabolomics and lipidomics quantify metabolites and lipids, such as ceramides, to assess metabolic rewiring during thermogenesis.
Mitochondrial Function Assays
Seahorse respirometry and mitochondrial fission assays measure oxygen consumption and mitochondrial dynamics in adipocytes.
How CRISPR Can Be Used to Study GO:0120161 regulation of cold-induced thermogenesis
Knockout
CRISPR knockout of candidate genes in mice or adipocyte cell lines is used to determine loss-of-function effects on cold-induced thermogenesis. For example, FAM195A knockout mice exhibit impaired cold tolerance, and peroxisomal gene knockout blocks mitochondrial fission.
Point Mutation
Point mutations can be introduced to model human variants or to ablate specific phosphorylation sites. This helps dissect signaling pathways, such as mutating PKA phosphorylation sites in UCP1 or AC3.
Knock-in
Knock-in of tagged proteins (e.g., GFP, HA) allows visualization and immunoprecipitation of endogenous proteins. This is useful for studying localization and interactions of thermogenic regulators like CLSTN3β.
Overexpression
CRISPR activation (CRISPRa) or transgenic overexpression enables gain-of-function studies. Overexpressing CLSTN3β enhances multilocularity and thermogenesis, while overexpressing Them1 impairs thermogenesis.
How EDITGENE Supports regulation of cold-induced thermogenesis Research
Researchers studying regulation of cold-induced thermogenesis-related genes often need to determine whether a candidate gene is causally involved in thermogenesis or merely correlated with it. This requires precise genetic manipulation, which CRISPR-based models can provide.
Contact EDITGENE today to design your custom CRISPR model for regulation of cold-induced thermogenesis research.
Frequently Asked Questions About regulation of cold-induced thermogenesis
What is GO:0120161?
GO:0120161 is the Gene Ontology term for regulation of cold-induced thermogenesis, defined as any process that modulates the frequency, rate or extent of cold-induced thermogenesis.
What genes are involved in regulation of cold-induced thermogenesis?
Key genes include UCP1, FAM195A, CLSTN3β, HIF2α, ChREBP, Them1, and AC3, among others [1,2,3,4,6,7].
How does cold exposure trigger thermogenesis?
Cold exposure activates the sympathetic nervous system, leading to norepinephrine release and cAMP signaling in brown adipose tissue, which activates thermogenic gene expression.
What is the role of brown adipose tissue in cold-induced thermogenesis?
Brown adipose tissue dissipates energy as heat through UCP1-mediated mitochondrial uncoupling, and its activity is regulated by numerous factors.
What diseases are associated with impaired cold-induced thermogenesis?
Impaired thermogenesis is linked to obesity, insulin resistance, type 2 diabetes, and cardiovascular disease [4,5].
How can CRISPR be used to study cold-induced thermogenesis?
CRISPR knockout, knock-in, and overexpression models allow causal testing of candidate genes in adipocytes and mice [1,2,3,4,6,7].
What is the role of FAM195A in thermogenesis?
FAM195A is an RNA-binding protein that regulates mRNA stability of thermogenic genes; its knockout impairs cold tolerance.
How does CLSTN3β regulate thermogenesis?
CLSTN3β enforces adipocyte multilocularity, promoting lipid utilization and efficient thermogenesis.
What is the function of HIF2α in adipose tissue?
HIF2α promotes ceramide catabolism, which suppresses atherosclerosis and supports thermogenesis.
What methods are used to study regulation of cold-induced thermogenesis?
Common methods include RNA-seq, ChIP-seq, lipidomics, Seahorse respirometry, and cold tolerance tests [1,2,4,6].
Conclusion
Regulation of cold-induced thermogenesis (GO:0120161) is a complex biological process essential for energy homeostasis and survival in cold environments. Key regulators such as FAM195A, CLSTN3β, HIF2α, ChREBP, and AC3 have been identified through recent studies, revealing diverse mechanisms from RNA stability to mitochondrial dynamics [1,2,3,4,6,7]. Dysregulation of this process contributes to obesity and metabolic diseases, making it a promising therapeutic target. CRISPR-based models are indispensable for dissecting causal roles of candidate genes and for discovering new regulators. EDITGENE offers comprehensive CRISPR services to support research in this field.
References
- 1. Park H et al.. 2019. Peroxisome-derived lipids regulate adipose thermogenesis by mediating cold-induced mitochondrial fission.. J Clin Invest 129(2):694-711 PMID: 30511960
- 2. Cannavino J et al.. 2021. Regulation of cold-induced thermogenesis by the RNA binding protein FAM195A.. Proc Natl Acad Sci U S A 118(23) PMID: 34088848
- 3. Qian K et al.. 2023. CLSTN3β enforces adipocyte multilocularity to facilitate lipid utilization.. Nature 613(7942):160-168 PMID: 36477540
- 4. Zhang X et al.. 2019. Adipocyte Hypoxia-Inducible Factor 2α Suppresses Atherosclerosis by Promoting Adipose Ceramide Catabolism.. Cell Metab 30(5):937-951.e5 PMID: 31668872
- 5. Choe SS et al.. 2016. Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders.. Front Endocrinol (Lausanne) 7:30 PMID: 27148161
- 6. Xu X et al.. 2024. ChREBP-mediated up-regulation of Them1 coordinates thermogenesis with glycolysis and lipogenesis in response to chronic stress.. Sci Signal 17(865):eadk7971 PMID: 39626011
- 7. Khani S et al.. 2024. Cold-induced expression of a truncated adenylyl cyclase 3 acts as rheostat to brown fat function.. Nat Metab 6(6):1053-1075 PMID: 38684889
- 8. van Marken Lichtenbelt WD et al.. 2003. Cold-induced metabolism.. Curr Opin Clin Nutr Metab Care 6(4):469-75 PMID: 12806223
