Endogenous GDF15 and FGF21 additively alleviate hepatic steatosis and insulin resistance in obese mice

Patel, Satish; Haider, Afreen; Álvarez-Guaita, Anna; Bidault, Guillaume; Moustafa, Julia S. El-Sayed; Guiu-Jurado, Esther; Tadross, John; Warner, Jamie H.; Harrison, James R.; Virtue, Samuel; Scurria, Fabio; Zvetkova, Ilona; Blüher, Matthias; Small, Kerrin S.; O’Rahilly, Stephen; Savage, David B.

doi:10.1101/2022.06.08.495255

Cited by 3 publications

(2 citation statements)

References 123 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This likely reflects the fact that affected humans also have fatty liver disease and diabetes, both strongly associated with elevated stress hormone levels 71,72 . In keeping with this, we have shown in mice that the liver is the predominant source of circulating FGF21 and GDF15, with little or no contribution from adipose tissue 73 .…”

Section: Discussionsupporting

confidence: 74%

A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion

Mann

Duan

Álvarez-Guaita

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in MFN2, encoding mitofusin-2. How this selective perturbation of mitochondrial function leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this, Mfn2R707W/R707W knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation by isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation perturbs mitochondrial morphology and activates the integrated stress response selectively in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response.

show abstract

Section: Discussionsupporting

confidence: 74%

A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion

Mann

Duan

Álvarez-Guaita

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…No clear evidence of increased tumour GDF15 expression was observed and no significant genomic amplification of the GDF15 locus was detected, however, GDF15 is also known to be produced in diverse tissue sites, including liver and kidney, which may act as alternative potential sources of pathological secretion. 65 , 71 . Furthermore, GDF15 is subject to differential rates of production and clearance that are mediated by other factors, such as hepatic stabilin-1 and -2 72 .…”

Section: Discussionmentioning

confidence: 99%

Body composition and lung cancer-associated cachexia in TRACERx

Al‐Sawaf

Weiss²,

Skrzypski³

et al. 2023

Nat Med

Self Cite

View full text Add to dashboard Cite

Cancer-associated cachexia (CAC) is a major determinant of morbidity and mortality in patients with non-small cell lung cancer (NSCLC). Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate possible biological processes and mediators that contribute to the development of CAC. Computed tomography-based (CT) body composition analysis of 651 patients in TRACERx suggested that patients with low skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, represented by the bottom 20 th percentile, had significantly shorter lung cancer-specific survival (LCSS) and overall survival (OS). This finding was validated in 420 patients in the independent Boston Lung Cancer Study. In a longitudinal subset of 272 patients in TRACERx who experienced disease relapse, loss of adipose tissue, skeletal muscle, or body weight in the interval between diagnosis and relapse, was significantly associated with shorter LCSS and OS. Patients with one or more features encompassing loss of adipose or muscle tissue, or BMI-adjusted weight loss according to specific thresholds were classified as having developed CAC and were found to have distinct tumour genomic and transcriptomic profiles compared with patients who did not develop such features at relapse. Primary NSCLCs from patients in the CAC group were characterised by enrichment of inflammatory signalling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumours included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3 . In an exploratory analysis of putative circulating cachexia mediators performed in a subset of 256 baseline and relapse plasma samples from TRACERx, proteomic analysis revealed a significant association between circulating GDF15 and loss of body weight, skeletal muscle, and adipose tissue at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.

show abstract

A mouse model of human mitofusin-2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion

Mann

Duan

Patel

et al. 2023

eLife

View full text Add to dashboard Cite

Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in MFN2, encoding mitofusin 2. How the resulting selective form of mitochondrial dysfunction leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this, Mfn2R707W/R707W knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation measured in isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation selectively perturbs mitochondrial morphology and activates the integrated stress response in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response.

show abstract

Endogenous GDF15 and FGF21 additively alleviate hepatic steatosis and insulin resistance in obese mice

Cited by 3 publications

References 123 publications

A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion

A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion

Body composition and lung cancer-associated cachexia in TRACERx

A mouse model of human mitofusin-2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion

Contact Info

Product

Resources

About