Cysteine 253 of UCP1 regulates energy expenditure and sex-dependent adipose tissue inflammation

Mills, Evanna L.; Harmon, Cathal; Jedrychowski, Mark P.; Xiao, Haopeng; Gruszczyk, Anja V.; Bradshaw, Gary A.; Tran, Nhien; Garrity, Ryan; Laznik-Bogoslavski, Dina; Szpyt, John; Prendeville, Hannah; Lynch, Lydia; Murphy, Michael P.; Gygi, Steven P.; Spiegelman, Bruce M.; Chouchani, Edward T.

doi:10.1016/j.cmet.2021.11.003

Cited by 35 publications

(31 citation statements)

References 106 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 118 – 120 Besides, thermogenic adipocytes also have an impact on immune cells through releasing meteorin-like hormone (Metrnl) which promotes eosinophil activation to produce IL-4, leading to the recruitment of alternatively activated M2 macrophages and the increased expression of anti-inflammatory gene programs. 121 – 123 …”

Section: The Developmental Origin and Anatomical Location Of Thermoge...mentioning

confidence: 99%

The evolving view of thermogenic fat and its implications in cancer and metabolic diseases

Yin

Chen

Ruze

et al. 2022

Sig Transduct Target Ther

View full text Add to dashboard Cite

The incidence of metabolism-related diseases like obesity and type 2 diabetes mellitus has reached pandemic levels worldwide and increased gradually. Most of them are listed on the table of high-risk factors for malignancy, and metabolic disorders systematically or locally contribute to cancer progression and poor prognosis of patients. Importantly, adipose tissue is fundamental to the occurrence and development of these metabolic disorders. White adipose tissue stores excessive energy, while thermogenic fat including brown and beige adipose tissue dissipates energy to generate heat. In addition to thermogenesis, beige and brown adipocytes also function as dynamic secretory cells and a metabolic sink of nutrients, like glucose, fatty acids, and amino acids. Accordingly, strategies that activate and expand thermogenic adipose tissue offer therapeutic promise to combat overweight, diabetes, and other metabolic disorders through increasing energy expenditure and enhancing glucose tolerance. With a better understanding of its origins and biological functions and the advances in imaging techniques detecting thermogenesis, the roles of thermogenic adipose tissue in tumors have been revealed gradually. On the one hand, enhanced browning of subcutaneous fatty tissue results in weight loss and cancer-associated cachexia. On the other hand, locally activated thermogenic adipocytes in the tumor microenvironment accelerate cancer progression by offering fuel sources and is likely to develop resistance to chemotherapy. Here, we enumerate current knowledge about the significant advances made in the origin and physiological functions of thermogenic fat. In addition, we discuss the multiple roles of thermogenic adipocytes in different tumors. Ultimately, we summarize imaging technologies for identifying thermogenic adipose tissue and pharmacologic agents via modulating thermogenesis in preclinical experiments and clinical trials.

show abstract

Section: The Developmental Origin and Anatomical Location Of Thermoge...mentioning

confidence: 99%

The evolving view of thermogenic fat and its implications in cancer and metabolic diseases

Yin

Chen

Ruze

et al. 2022

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

“…The mitochondria of iBAT in these UCP1-null mice also display significant alterations in mitochondrial morphology, considerable reduction in the protein abundance of electron transport chain subunits, greater sensitivity to ROS-induced dysfunction and activation of the immune response ( 521 ). Very recently, a novel UCP1 cysteine-253-null mouse was generated to induce an inactive conformation of UCP1 ( 522 ). UCP1 cysteine-253-null mice display lower whole body thermogenesis at 4 °C, but not at 28 or 22 °C compared to wild-type mice.…”

Section: Physiological Roles Of Brown Adipose Tissuementioning

confidence: 99%

“…This new model is free of the profound respiratory chain protein defects of the UCP1-null mice and of any accumulation of excess fat mass on an HFD. Furthermore, only males display glucose intolerance and liver and systemic inflammation with an HFD, which are corrected on estrogen administration ( 522 ).…”

Section: Physiological Roles Of Brown Adipose Tissuementioning

confidence: 99%

Brown Adipose Tissue—A Translational Perspective

et al. 2022

View full text Add to dashboard Cite

Brown adipose tissue (BAT) displays the unique capacity to generate heat through uncoupled oxidative phosphorylation that makes it a very attractive therapeutic target for cardiometabolic diseases. Here, we review BAT cellular metabolism, its regulation by the central nervous and endocrine systems and circulating metabolites, the plausible roles of this tissue in human thermoregulation, energy balance and cardiometabolic disorders, and the current knowledge on its pharmacological stimulation in humans. The current definition and measurement of BAT in human studies relies almost exclusively on BAT glucose uptake from positron emission tomography (PET) with 18F-fluorodeoxiglucose ( 18FDG), which can be dissociated from BAT thermogenic activity, as for example in insulin resistant states. The most important energy substrate for BAT thermogenesis is its intracellular fatty acid content mobilized from sympathetic stimulation of intracellular triglyceride (TG) lipolysis. This lipolytic BAT response is intertwined with that of white adipose and other metabolic tissues, and cannot be independently stimulated with the drugs tested thus far. BAT is an interesting and biologically plausible target that has yet to be fully and selectively activated to increase the body’s thermogenic response and shift energy balance. The field of human BAT research is in need of methods able to directly, specifically and reliably measure BAT thermogenic capacity while also tracking the related thermogenic responses in white adipose and other tissues. Until this is achieved, uncertainty will remain about the role played by this fascinating tissue in human cardiometabolic diseases.

show abstract

“…Besides, the improvement of metabolic phenotype of GPSM1 f/f ; Lyz2-cre females compared with the counterparts, is weaker than males. As GPSM1 knockdown had downregulated trend of ESRRA mRNA expression in our RNA-Seq data (NODE: OEP003692), and the estrogen receptor signaling is known to confer systemic protective metabolic effects in the context of obesity 61 , 62 , thus, we speculate that estrogen signaling in females may in part underlie the observed sex difference. More molecular mechanisms need further investigation.…”

Section: Discussionmentioning

confidence: 70%

GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages

Yan

Zhang

et al. 2022

Nat Commun

View full text Add to dashboard Cite

G-protein-signaling modulator 1 (GPSM1) exhibits strong genetic association with Type 2 diabetes (T2D) and Body Mass Index in population studies. However, how GPSM1 carries out such control and in which types of cells are poorly understood. Here, we demonstrate that myeloid GPSM1 promotes metabolic inflammation to accelerate T2D and obesity development. Mice with myeloid-specific GPSM1 ablation are protected against high fat diet-induced insulin resistance, glucose dysregulation, and liver steatosis via repression of adipose tissue pro-inflammatory states. Mechanistically, GPSM1 deficiency mainly promotes TNFAIP3 transcription via the Gαi3/cAMP/PKA/CREB axis, thus inhibiting TLR4-induced NF-κB signaling in macrophages. In addition, we identify a small-molecule compound, AN-465/42243987, which suppresses the pro-inflammatory phenotype by inhibiting GPSM1 function, which could make it a candidate for metabolic therapy. Furthermore, GPSM1 expression is upregulated in visceral fat of individuals with obesity and is correlated with clinical metabolic traits. Overall, our findings identify macrophage GPSM1 as a link between metabolic inflammation and systemic homeostasis.

show abstract

Cysteine 253 of UCP1 regulates energy expenditure and sex-dependent adipose tissue inflammation

Cited by 35 publications

References 106 publications

The evolving view of thermogenic fat and its implications in cancer and metabolic diseases

The evolving view of thermogenic fat and its implications in cancer and metabolic diseases

Brown Adipose Tissue—A Translational Perspective

GPSM1 impairs metabolic homeostasis by controlling a pro-inflammatory pathway in macrophages

Contact Info

Product

Resources

About