GO:0120163 negative regulation of cold-induced thermogenesis: Metabolic Brake Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0120163 (negative regulation of cold-induced thermogenesis) describes any process that stops, prevents, or reduces the rate of cold-induced thermogenesis, the heat-generating program of brown and beige adipocytes.
• Cold-induced thermogenesis is executed by brown adipose tissue (BAT) and beige adipocytes, and its suppression is a major driver of reduced energy expenditure in obesity and metabolic disease.
• Key negative regulators include the chemerin-CMKLR1 axis, selenoprotein P (SELENOP), PNPLA7, and the CBP/p300-HDAC3-CREBZF acetylation module.
• Positive regulators such as CELF1, which stabilizes Dio2 mRNA, and Nr4a1, a cold-induced effector, provide the counterbalance that defines the negative regulation term.
• Human studies show that active BAT determines cold-induced energy expenditure and oxylipin profiles, making negative regulation of CIT clinically measurable.
• CRISPR knockout, knock-in, point-mutation, and overexpression models are essential to causally test whether a candidate gene negatively regulates cold-induced thermogenesis.
Description
GO:0120163, negative regulation of cold-induced thermogenesis, is a biological process Gene Ontology term defined as any process that stops, prevents, or reduces the rate of cold-induced thermogenesis. Cold-induced thermogenesis is the adaptive production of heat in brown adipose tissue (BAT) and beige adipocytes in response to cold exposure, and it is a major component of energy expenditure in mammals. Because excessive thermogenesis is energetically costly, organisms have evolved inhibitory circuits that restrain this program; these circuits are precisely what GO:0120163 annotates. The term matters because the balance between activation and inhibition of cold-induced thermogenesis determines whole-body energy balance. When negative regulation is too strong, energy expenditure falls and obesity risk rises, whereas when it is too weak, excessive heat production and metabolic stress can occur. Human studies have shown that the presence of active BAT determines cold-induced energy expenditure and circulating oxylipin profiles, confirming that this process is measurable and physiologically relevant in people. Mechanistically, negative regulation of cold-induced thermogenesis is not a single pathway but a convergence of endocrine, immune, mitochondrial, and epigenetic brakes. The chemerin-CMKLR1 axis limits thermogenesis by controlling a beige adipocyte/IL-33/type 2 innate immunity circuit, selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat, and glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF provides an epigenetic brake. Understanding these mechanisms is essential for therapeutic targeting of adipose tissue.
negative regulation of cold-induced thermogenesis At A Glance
| GO ID | GO:0120163 |
|---|---|
| GO term | negative regulation of cold-induced thermogenesis |
| Ontology | biological_process |
| Synonym | negative regulation of CIT |
| Major function | Suppression of adaptive heat production in brown and beige adipose tissue |
| Definition | Any process that stops, prevents, or reduces the rate of cold-induced thermogenesis |
| Related process | Cold-induced thermogenesis (positive counterpart) |
| Key tissues | Brown adipose tissue, beige adipocytes, liver |
| Representative regulators | CMKLR1, SELENOP, PNPLA7, CREBZF, HDAC3, CD38 |
What Is GO:0120163?
In plain terms, GO:0120163 describes the biological brakes on cold-induced heat production. The QuickGO definition states: any process that stops, prevents, or reduces the rate of cold-induced thermogenesis. This means the term covers inhibitory signaling molecules, transcriptional and epigenetic repressors, mitochondrial quality-control factors, and endocrine or immune circuits that suppress BAT and beige adipocyte thermogenesis. It is the logical inverse of positive regulation of cold-induced thermogenesis and is annotated to biological_process.
Why Is negative regulation of cold-induced thermogenesis Important in Cell Biology?
Negative regulation of cold-induced thermogenesis is important because it sets the upper limit of energy expenditure and therefore directly influences obesity, insulin resistance, and cardiometabolic risk. The chemerin-CMKLR1 axis limits thermogenesis by controlling a beige adipocyte/IL-33/type 2 innate immunity circuit, linking immune signaling to metabolic restraint. Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat, showing that redox balance is a negative regulator. Liver CD38 regulates metabolic pathways during cold-induced thermogenesis in mice, indicating cross-organ control. In humans, the presence of active BAT determines cold-induced energy expenditure and oxylipin profiles, so negative regulation is clinically measurable. Finally, glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF provides a druggable epigenetic brake.
• Defines the inhibitory arm of thermogenesis, which determines whole-body energy expenditure.
• Links obesity and insulin resistance to insufficient or excessive thermogenic restraint.
• Connects immune circuits (IL-33, type 2 innate immunity) to metabolic suppression.
• Implicates redox biology and selenoprotein P in brown fat dysfunction.
• Reveals mitochondrial quality control (PNPLA7-Parkin mitophagy) as a browning brake.
• Highlights epigenetic acetylation (CBP/p300, HDAC3, CREBZF) as a regulatory node.
• Provides cross-organ regulation through liver CD38 and NAD+ metabolism.
• Offers human-relevant biomarkers via BAT activity and oxylipin profiling.
• Supports therapeutic strategies to release the brake and increase energy expenditure.
• Requires causal CRISPR models to distinguish correlation from causation.
What Happens During negative regulation of cold-induced thermogenesis?
Cold sensing and the thermogenic program
In simple terms: When it gets cold, brown fat turns on a heat-making program, and negative regulation is the set of signals that turn it down.
Cold exposure activates brown adipose tissue and beige adipocytes to produce heat, a process that requires transcriptional and post-transcriptional support such as CELF1-mediated stabilization of Dio2 mRNA. Nr4a1 was identified as a cold-induced effector of brown fat thermogenesis, providing an early molecular marker of the activated state. Negative regulation of cold-induced thermogenesis acts on this activated state to reduce the rate of heat production.
Endocrine and immune brakes
In simple terms: Hormone-like signals and immune cells can put the brakes on heat production.
The chemerin-CMKLR1 axis limits thermogenesis by controlling a beige adipocyte/IL-33/type 2 innate immunity circuit, demonstrating that endocrine-immune crosstalk is a core negative regulatory mechanism. This circuit restrains beige adipocyte activation and therefore reduces cold-induced thermogenesis.
Redox and mitochondrial quality-control brakes
In simple terms: Chemical stress and recycling of damaged mitochondria can shut down heat production.
Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat, showing that an altered redox environment negatively regulates thermogenesis. PNPLA7 mediates Parkin-mitochondrial recruitment in adipose tissue for mitophagy and inhibits browning, linking mitochondrial quality control to negative regulation of thermogenesis.
Epigenetic and transcriptional brakes
In simple terms: Chemical tags on DNA-packaging proteins can lock the heat-making genes in the off position.
Glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF provides an epigenetic mechanism that restrains browning. This acetylation switch integrates nutrient status with negative regulation of cold-induced thermogenesis.
Cross-organ metabolic control
In simple terms: Organs such as the liver send signals that influence how much heat brown fat makes.
Liver CD38 regulates metabolic pathways during cold-induced thermogenesis in mice, indicating that hepatic NAD+ metabolism participates in the systemic control of thermogenesis. This cross-organ regulation can either support or restrain cold-induced heat production depending on context.
Key Genes Involved in GO:0120163 negative regulation of cold-induced thermogenesis
The following genes and proteins have been experimentally linked to the regulation of cold-induced thermogenesis and its negative control.
| Gene | Major Role | Research Relevance |
|---|---|---|
| CMKLR1 | Receptor for chemerin that limits thermogenesis via beige adipocyte/IL-33/type 2 innate immunity | Negative regulator of beige adipocyte activation |
| SELENOP | Selenoprotein P mediates reductive stress and impairs cold-induced thermogenesis | Redox brake in brown fat |
| PNPLA7 | Mediates Parkin-mitochondrial recruitment for mitophagy and inhibits browning | Mitochondrial quality-control brake |
| CREBZF | Transcription factor regulated by CBP/p300- and HDAC3-mediated acetylation | Epigenetic brake on adipose browning |
| HDAC3 | Deacetylase that reversibly acetylates CREBZF | Epigenetic regulator of browning |
| CBP/p300 | Acetyltransferases that reversibly acetylate CREBZF | Epigenetic regulator of browning |
| CD38 | Liver NAD+ -consuming enzyme regulating metabolic pathways during cold-induced thermogenesis | Cross-organ metabolic regulator |
| CELF1 | RNA-binding protein that stabilizes Dio2 mRNA and promotes beiging | Positive regulator providing counterbalance |
| Dio2 | Type 2 deiodinase supporting thermogenic gene program | Target of CELF1 stabilization |
| Nr4a1 | Cold-induced effector of brown fat thermogenesis | Marker of activated thermogenesis |
| IL-33 | Cytokine in the beige adipocyte/type 2 innate immunity circuit | Immune brake component |
| Parkin | E3 ubiquitin ligase recruited to mitochondria by PNPLA7 | Mitophagy regulator |
| UCP1 | Uncoupling protein 1, canonical thermogenic effector | Readout of thermogenesis in BAT |
| Chemerin | Adipokine ligand for CMKLR1 | Endocrine brake on thermogenesis |
How Is negative regulation of cold-induced thermogenesis Regulated?
Negative regulation of cold-induced thermogenesis is itself regulated at multiple levels. Nutrient status, including glucose availability, controls CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF, which in turn restrains adipose tissue browning. Redox balance is another layer, because selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat. Mitochondrial quality control through PNPLA7-Parkin-mediated mitophagy inhibits browning, adding a degradation-dependent regulatory step. Immune and endocrine circuits, particularly the chemerin-CMKLR1 axis acting through IL-33 and type 2 innate immunity, provide systemic regulation of beige adipocyte activity. Finally, hepatic CD38 and NAD+ metabolism contribute to cross-organ regulation of cold-induced thermogenesis in mice.
negative regulation of cold-induced thermogenesis and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CMKLR1 | Obesity and impaired beige adipocyte thermogenesis | Knockout mouse and adipocyte-specific deletion |
| SELENOP | Reductive stress and brown fat dysfunction | Overexpression and knockout models |
| PNPLA7 | Mitophagy-associated inhibition of browning | Knockout and tagged knock-in for mitophagy tracking |
| CREBZF | Glucose-linked suppression of adipose browning | Acetylation-site point-mutation knock-in |
| CD38 | Liver-driven metabolic regulation during cold exposure | Liver-specific knockout |
Obesity and insulin resistance
Because negative regulation of cold-induced thermogenesis reduces energy expenditure, its overactivity contributes to positive energy balance and obesity. The chemerin-CMKLR1 axis limits thermogenesis and represents a target for increasing energy expenditure. Glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF links nutrient excess to suppressed browning, a mechanism relevant to insulin resistance.
Metabolic syndrome and BAT dysfunction
Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat, connecting redox imbalance to BAT dysfunction and metabolic syndrome. PNPLA7-mediated mitophagy inhibits browning, suggesting that impaired mitochondrial quality control contributes to reduced thermogenic capacity. Human data show that the presence of active BAT determines cold-induced energy expenditure and oxylipin profiles, providing a clinical readout of thermogenic capacity.
Cross-organ metabolic disease
Liver CD38 regulates metabolic pathways during cold-induced thermogenesis in mice, indicating that hepatic NAD+ metabolism influences systemic thermogenesis and may contribute to metabolic disease. This cross-organ axis expands the therapeutic scope of GO:0120163 beyond adipose tissue alone.
From negative regulation of cold-induced thermogenesis-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is the candidate gene a negative regulator of cold-induced thermogenesis? | Knockout model with cold-exposure challenge |
| Does a specific acetylation site on CREBZF mediate the brake? | Point-mutation knock-in of the acetylation site |
| Where and when is the protein expressed during cold exposure? | Tagged knock-in for imaging and proteomics |
| Does forced expression of the candidate gene suppress browning? | Overexpression model in adipocytes or mice |
| Does loss of the gene increase energy expenditure? | Knockout with metabolic cage and BAT activity readouts |
| Does the gene act cell-autonomously in beige adipocytes? | Adipocyte-specific conditional knockout |
How to Study the negative regulation of cold-induced thermogenesis Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Transcriptome changes during cold exposure | Identify negative regulators of thermogenesis |
| Metabolic cage / indirect calorimetry | Energy expenditure and substrate use | Quantify thermogenic capacity |
| BAT imaging (PET/CT or infrared) | Brown adipose tissue activity | Human and mouse thermogenesis readouts |
| Mitophagy flux assays | Mitochondrial turnover | Study PNPLA7-Parkin axis |
| Redox assays | Oxidative and reductive stress | Study selenoprotein P effects |
| Acetylation immunoblotting | Site-specific acetylation of CREBZF | Study CBP/p300 and HDAC3 regulation |
| Oxylipin profiling | Circulating lipid mediators | Human BAT activity correlation |
| Cold-exposure challenge | Physiological thermogenic response | Phenotype negative regulators in vivo |
Transcriptomic and epitranscriptomic profiling
RNA-seq and related approaches reveal how negative regulators reshape the thermogenic transcriptome. CELF1 was shown to promote beiging of white fat by stabilizing Dio2 mRNA, illustrating the value of RNA-level analysis. Cold-induced effectors such as Nr4a1 were identified through expression profiling of brown fat.
Metabolic and thermogenic phenotyping
Cold-exposure experiments combined with metabolic cages, BAT imaging, and oxylipin profiling quantify thermogenic capacity. Human studies demonstrate that active BAT determines cold-induced energy expenditure and oxylipin profiles. Mouse models of liver CD38 regulation further show how systemic metabolic pathways can be measured during cold-induced thermogenesis.
Mitochondrial and redox assays
Mitophagy and redox assays are essential for studying negative regulation. PNPLA7 mediates Parkin-mitochondrial recruitment for mitophagy and inhibits browning, requiring mitochondrial imaging and flux assays. Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis, requiring redox-sensitive readouts.
Epigenetic and acetylation analysis
Acetylation-specific antibodies and chromatin assays dissect epigenetic brakes. Glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF requires acetylation-site mapping and HDAC3 inhibition studies.
How CRISPR Can Be Used to Study GO:0120163 negative regulation of cold-induced thermogenesis
Knockout
CRISPR knockout of candidate negative regulators such as CMKLR1, SELENOP, PNPLA7, or CD38 allows direct testing of whether loss of the gene increases cold-induced thermogenesis. Knockout models are the primary tool for establishing causality in GO:0120163 research.
Point Mutation
Point-mutation knock-in can test whether specific residues, such as acetylation sites on CREBZF, are required for the negative regulation of cold-induced thermogenesis. This approach separates catalytic or modification-dependent functions from scaffolding roles.
Knock-in
Tagged knock-in of genes such as PNPLA7 enables tracking of protein localization and mitophagy recruitment in adipose tissue. Knock-in reporters also allow precise measurement of cold-induced expression dynamics.
Overexpression
Overexpression of negative regulators such as SELENOP or the chemerin-CMKLR1 axis components can suppress browning and reduce cold-induced thermogenesis, providing gain-of-function evidence. Overexpression models complement knockout studies to establish bidirectional causality.
How EDITGENE Supports negative regulation of cold-induced thermogenesis Research
Researchers studying negative regulation of cold-induced thermogenesis-related genes often need to determine whether a candidate gene is causally involved in suppressing thermogenesis or is merely correlated with it. Establishing causality requires precise genetic models that can remove, modify, or amplify the gene of interest in relevant adipose and metabolic tissues.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of cold-induced thermogenesis research.
Frequently Asked Questions About negative regulation of cold-induced thermogenesis
What is GO:0120163?
GO:0120163 is the Gene Ontology biological process term for negative regulation of cold-induced thermogenesis, defined as any process that stops, prevents, or reduces the rate of cold-induced thermogenesis.
What is negative regulation of cold-induced thermogenesis?
It is the set of biological mechanisms that suppress adaptive heat production in brown and beige adipose tissue, including endocrine, immune, redox, mitochondrial, and epigenetic brakes.
What genes are involved in negative regulation of cold-induced thermogenesis?
Key genes include CMKLR1, SELENOP, PNPLA7, CREBZF, HDAC3, CBP/p300, and CD38, while CELF1, Dio2, and Nr4a1 represent positive or supporting regulators.
How does the chemerin-CMKLR1 axis limit thermogenesis?
The chemerin-CMKLR1 axis limits thermogenesis by controlling a beige adipocyte/IL-33/type 2 innate immunity circuit.
What role does selenoprotein P play in brown fat?
Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat.
How does PNPLA7 inhibit browning?
PNPLA7 mediates Parkin-mitochondrial recruitment in adipose tissue for mitophagy and inhibits browning.
How is CREBZF acetylation linked to adipose browning?
Glucose regulation of adipose tissue browning occurs through CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF.
Does liver CD38 affect cold-induced thermogenesis?
Yes, liver CD38 regulates metabolic pathways during cold-induced thermogenesis in mice.
Can human BAT activity be measured?
Yes, the presence of active brown adipose tissue determines cold-induced energy expenditure and oxylipin profiles in humans.
What CRISPR models are used to study negative regulation of cold-induced thermogenesis?
Knockout, point-mutation knock-in, tagged knock-in, and overexpression models are used to test causality for genes such as CMKLR1, SELENOP, PNPLA7, CREBZF, and CD38.
Conclusion
GO:0120163, negative regulation of cold-induced thermogenesis, captures the inhibitory circuits that restrain heat production in brown and beige adipose tissue. These circuits span endocrine-immune signaling through the chemerin-CMKLR1 axis, redox stress via selenoprotein P, mitochondrial quality control through PNPLA7-Parkin, epigenetic control by CBP/p300-HDAC3-CREBZF, and cross-organ regulation by liver CD38. Positive regulators such as CELF1 and Nr4a1 define the counterbalance that makes negative regulation meaningful. Because active BAT determines cold-induced energy expenditure and oxylipin profiles in humans, this process is directly relevant to obesity and metabolic disease. Causal dissection of these mechanisms requires precise CRISPR models, including knockout, point-mutation, knock-in, and overexpression approaches, which allow researchers to determine whether a candidate gene truly brakes thermogenesis.
References
- 1. Benzi A et al.. 2022. Role of Liver CD38 in the Regulation of Metabolic Pathways during Cold-Induced Thermogenesis in Mice.. Cells 11(23) PMID: 36497069
- 2. Ji X et al.. 2025. PNPLA7 mediates Parkin-mitochondrial recruitment in adipose tissue for mitophagy and inhibits browning.. Nat Commun 16(1):6651 PMID: 40681495
- 3. Zeng T et al.. 2025. Adipocyte RNA-binding protein CELF1 promotes beiging of white fat through stabilizing Dio2 mRNA.. Nat Commun 16(1):7414 PMID: 40789858
- 4. Lin Y et al.. 2021. The chemerin-CMKLR1 axis limits thermogenesis by controlling a beige adipocyte/IL-33/type 2 innate immunity circuit.. Sci Immunol 6(61) PMID: 34330814
- 5. Oo SM et al.. 2022. Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat.. Cell Rep 38(13):110566 PMID: 35354056
- 6. Kanzleiter T et al.. 2005. Evidence for Nr4a1 as a cold-induced effector of brown fat thermogenesis.. Physiol Genomics 24(1):37-44 PMID: 16219868
- 7. 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
- 8. Cui A et al.. 2024. Glucose regulation of adipose tissue browning by CBP/p300- and HDAC3-mediated reversible acetylation of CREBZF.. Proc Natl Acad Sci U S A 121(16):e2318935121 PMID: 38588421
