Cell Metab impaired thermogenesis in cold environments and gender-dependent systemic inflammation are all related to UCP1

Written | Qi In rodents and humans, the most typical interventions to drive brown adipose tissue (BAT) heat production are cold exposure and β-adrenergic receptor activation
.

These stimuli can cause BAT to remove glucose and fatty acids from the blood, increase energy expenditure and prevent insulin resistance
.

The above interventions partially activate a protein uniquely expressed in BAT and beige fat, the thermogenic effector uncoupling protein 1 (uncoupling protein 1, UCP1) to initiate thermogenesis of adipose tissue, and UCP1 remains inactive under basal conditions State, but when activated, it will cause protons to leak through the inner mitochondrial membrane, thereby significantly increasing the catabolism of reducing substrates from glucose and fat [1, 2]
.

Studies have shown that UCP1-deficient mice lack thermogenesis response to BAT adrenergic receptor agonists.
However, considering that UCP1 loss will lead to the depletion of most components of the mitochondrial electron transport chain (ETC) in BAT, UCP1-deficient mice The interpretation of the phenotype is confusing and can be attributed to ETC consumption or loss of UCP1 protein itself
.

Therefore, it is necessary to establish a genetic model that can specifically destroy UCP1 activation without consuming ETC to evaluate its importance in thermogenesis, physiological and metabolic diseases
.

On December 2, 2021, the Edward T.
Chouchani team from the Dana-Farber Cancer Institute in the United States published an article titled Cysteine ​​253 of UCP1 regulates energy expenditure and sex-dependent adipose tissue inflammation in Cell Metabolism.
, The team generated a mouse model that can selectively destroy UCP1 in vivo and found that UCP1 C253A can cause mice to exhibit a significantly impaired thermogenic response, while only causing a large number of immune cell infiltrations in the adipose tissue and liver of male mice.
And systemic inflammatory response, the increase of the systemic level of estrogen can reverse this pathological change
.

This gender dimorphism of UCP1 supports the view that women have a protective mechanism against metabolic diseases (such as T2D).
At the same time, UCP1 C253 is also identified as a modulator of acute thermogenesis and sex-dependent tissue inflammation
.

The team has previously reported that thermogenesis ROS can reversibly modify the C253 site of UCP1, and the structural model indicates that this site can stabilize the inactive conformation of UCP1 [3]
.

Based on these findings, the team generated a UCP1 C253A mouse model.
Quantitative proteomics showed that, unlike the previously reported UCP1 KO mouse BAT, UCP1 C253A BAT can maintain the entire library of mitochondrial metabolic proteins at WT levels under standard feeding conditions.
Expression
.

Subsequently, the mice were exposed to a series of acute thermogenic stimuli.
Compared with WT mice, UCP1 C253A mice showed significantly reduced oxygen consumption rate, CO2 release rate and energy consumption.
The infrared thermal imaging camera also showed that the mice The temperature of the entire backside is significantly reduced
.

These results all suggest that the thermogenic response of UCP1 C253A mice was significantly weakened when exposed to cold
.

Figure 1.
UCP1 C253A mice have impaired thermogenesis during cold exposure.
Interestingly, after being given a high-fat, high-sucrose (HFHS) diet, although WT and C253A mice are difficult to distinguish between body weight and total fat, only Male C253A mice showed obvious glucose intolerance
.

Through 13C6-glucose tracking, it was found that the catabolism of glucose in the lower part of glycolysis in BAT was significantly impaired
.

Based on this gender difference, the authors performed a proteomic analysis on the white adipose tissue of mice fed with HFHS
.

In male C253A mice, the abundance of immune-related proteins that regulate immune cell phagocytosis, antigen processing and presentation, and neutrophil-mediated are significantly increased, while these pathways are not changed at all in female C253A mice, on the contrary, cause inflammation Several pathways including complement system proteins, mast cell secretion of granule proteins, etc.
were significantly down-regulated in female C253A mice
.

These findings indicate that UCP1 C253 has gender dimorphism in white adipose tissue inflammation
.

In addition, UCP1 C253A can also play a pro-inflammatory effect in tissues that do not express UCP1, such as liver and epididymal white adipose tissue
.

So how does the selective expression of UCP1 C253A in brown and beige fat affect local and systemic inflammation? Taking into account the interdependence between UCP1 and ROS, it can be inferred that oxidized mitochondrial-derived macromolecules act as mediators and are released into the circulation to cause systemic inflammation
.

Protein cysteine ​​residues are highly sensitive to changes in local ROS levels.
For this reason, the authors used the Cysteine ​​Reactive Phosphate Tag (CPT) method [4] to map the cysteine ​​oxidation state of the protein in BAT
.

The cysteine ​​oxidation state of hundreds of proteins in HFHS C253A BAT has changed, including the increase in the oxidation level of mitochondrial proteins and inflammation-related proteins, and a significant increase in circulating mtDNA
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If the mitochondrial targeting antioxidant MitoQ is supplemented in the HFHS diet, the above signs of inflammation can be significantly reversed
.

One question is, why does the systemic inflammatory response mediated by UCP1 C253A only occur in male mice but not in female mice? For this reason, the author speculates that estrogen signaling may play a role in protecting female mice from inflammation
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Before HFHS diet intervention, the authors implanted slow-release β-estradiol capsules under the skin of male mice
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The expression of inflammatory cytokines was still significantly increased in untreated male mice, and normalized to WT levels in the treated group.
The above-mentioned proteins related to regulation of immune cell phagocytosis, antigen processing and presentation, and neutrophil-mediated immunity were also Significantly reduced, suggesting that estrogen signaling plays a central role in antagonizing the inflammatory response in the adipose tissue of CP1 C253A mice
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As we all know, the incidence of T2D in premenopausal women is lower than that of men or postmenopausal women.
To a certain extent, it is considered to be the result of reduced inflammation in women through estrogen receptor signaling [5]
.

This study further found that the pharmacological increase in estrogen signaling in male mice reversed the inflammation caused by the absence of UCP1 C253 to a large extent, supporting the aforementioned view
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In summary, this study established a mouse model that can selectively disrupt UCP1 activation, indicating that UCP1 C253 is a key regulator of acute thermogenesis activation and systemic inflammation homeostasis, and has the ability to protect male mice from the pathogenesis of inflammation and metabolism.
Specific role
.

Original link: https://doi.
org/10.
1016/j.
cmet.
2021.
11.
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Chouchani, ET, Kazak, L.
, and Spiegelman, BM (2019).
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, Jedrychowski, MP, Lu, GZ, Erickson, BK, Szpyt, J.
, Pierce, KA, Laznik-Bogoslavski, D.
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, Jedrychowski, MP, Schweppe, DK, Huttlin, EL, Yu, Q.
, Heppner, DE, Li, J.
, Long, J.
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Davis, KE, D Neinast, M.
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, D Bills, J.
, A Zehr, J.
, Zeve, D.
, D Hahner, L.
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(2013).
The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis.
Mol.
Metab.
2, 227–242.
Instructions for reprinting 【Original Articles 】BioArt original articles, personal forwarding and sharing are welcome, reprinting is prohibited without permission, the copyright of all published works is owned by BioArt(2013).
The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis.
Mol.
Metab.
2, 227–242.
Instructions for reprinting [original articles] BioArt original articles, personal sharing is welcome, Reprinting is prohibited without permission, the copyright of all published works is owned by BioArt(2013).
The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis.
Mol.
Metab.
2, 227–242.
Instructions for reprinting [original articles] BioArt original articles, personal sharing is welcome, Reprinting is prohibited without permission, the copyright of all published works is owned by BioArt
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