The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases

Tsai, Vicky Wang-Wei; Husaini, Yasmin; Sainsbury, Amanda; Brown, David A.; Breit, Samuel N.

doi:10.1016/j.cmet.2018.07.018

Cited by 271 publications

(215 citation statements)

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“…Growth and Differentiation Factor 15 (GDF15), also known as NSAID-activated gene 1 (NAG-1) and macrophage inhibitory cytokine 1 (MIC-1), is a stress response cytokine and a distant member of the transforming growth factor beta (TGFb) superfamily (4). The role and effects of GDF15 are best documented in obesity and regulation of energy homeostasis (5).…”

Section: Introductionmentioning

confidence: 99%

CXCL5-mediated recruitment of neutrophils into the peritoneal cavity ofGdf15-deficient mice protects against abdominal sepsis

Santos

Colaço

Neves‐Costa

et al. 2019

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Sepsis is a life-threatening organ dysfunction condition caused by a dysregulated host response to an infection. Here we report that the circulating levels of growthdifferentiation factor-15 (GDF15) are strongly increased in septic shock patients and correlate with mortality. In mice, we find that peptidoglycan is a potent ligand that signals through the TLR2-Myd88 axis for the secretion of GDF15 and that Gdf15deficient animals are protected against abdominal sepsis due to increased chemokine CXC ligand 5 (CXCL5)-mediated recruitment of neutrophils into the peritoneum leading to better local bacterial control. Our results identify GDF15 as a potential target to improve sepsis treatment. Its inhibition should increase neutrophil recruitment to the site of infection and consequently lead to better pathogen control and clearance.Anorexia and weight loss are key features of the wasting syndrome that often accompanies late-stages of cancer and where GDF15 is known to play a critical role (12). These signs, including long-lasting loss of muscle mass, are also observed in sepsis (13). The common pathological features of both conditions led us to investigate whether GDF15 is increased in sepsis and if it plays a role in its pathophysiology.

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Section: Introductionmentioning

confidence: 99%

CXCL5-mediated recruitment of neutrophils into the peritoneal cavity ofGdf15-deficient mice protects against abdominal sepsis

Santos

Colaço

Neves‐Costa

et al. 2019

Preprint

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“…GDF15 is a distant member of the TGF-β superfamily. It is secreted, circulating in plasma as a 25 kDa homodimer [9, 10], and has become a novel exploratory biomarker of CMS because its circulating levels are increased in humans with metabolic syndrome [11, 14, 19] and in subjects with increased risk of CVD [12, 13]. In concert with human data, GDF15 levels do rise following a sustained high-fat diet or dietary amino acid imbalance in mice [57], and according to our present report (Fig 1G), GDF15 is significantly increased in the serum of obese ZSF1 rats.…”

Section: Discussionmentioning

confidence: 99%

“…In concert with human data, GDF15 levels do rise following a sustained high-fat diet or dietary amino acid imbalance in mice [57], and according to our present report (Fig 1G), GDF15 is significantly increased in the serum of obese ZSF1 rats. To date, GDF15 is positioned as a stress-induced hormone that mediates an aversive dietary response in preclinical species; when it was tested in obese mouse and non-human primate models, treatment resulted in significantly reduced body weight and food intake, increased energy expenditure, and improved glucose tolerance [14, 15].…”

Section: Discussionmentioning

confidence: 99%

“…Recently published studies in obese preclinical models demonstrated an aversive dietary response to GDF15 treatment, leading to an improvement in metabolic parameters. Thus, daily injections of GDF15 to mice for 14 days to 21 weeks resulted in significantly reduced body weight and food intake, increased energy expenditure, improved glucose tolerance, and reduced inflammatory cytokines [14]. Administration of human GDF15 to rodents via an adenovirus system and to obese monkeys via protein injections led to body weight loss and an improved metabolic profile [15].…”

Section: Introductionmentioning

confidence: 99%

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The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15

Stolina

Luo

Dwyer

et al. 2020

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19Cardiometabolic syndrome has become a global health issue. Heart failure is a common 20 comorbidity of cardiometabolic syndrome. Successful drug development to prevent 21 cardiometabolic syndrome and associated comorbidities requires preclinical models predictive 22 of human conditions. To characterize the heart failure component of cardiometabolic 2 23 syndrome, cardiometabolic, metabolic, and renal biomarkers were evaluated in obese and lean 24 ZSF1 20-to 22-week-old male rats. Cardiac function, exercise capacity, and left ventricular 25 gene expression were also analyzed. Obese ZSF1 rats exhibited multiple features of human 26 cardiometabolic syndrome by pathological changes in systemic renal, metabolic, and 27 cardiovascular disease circulating biomarkers. Hemodynamic assessment, echocardiography, 28 and decreased exercise capacity confirmed heart failure with preserved ejection fraction. RNA-29 seq results demonstrated changes in left ventricular gene expression associated with fatty acid 30 and branched chain amino acid metabolism, cardiomyopathy, cardiac hypertrophy, and heart 31 failure. Twelve weeks of growth differentiation factor 15 (GDF15) treatment significantly 32 decreased body weight, food intake, blood glucose, and triglycerides and improved exercise 33 capacity in obese ZSF1 males. Systemic cardiovascular injury markers were significantly 34 lower in GDF15-treated obese ZSF1 rats. Obese ZSF1 male rats represent a preclinical model 35 for human cardiometabolic syndrome with established heart failure with preserved ejection 36 fraction. GDF15 treatment mediated dietary response and demonstrated a cardioprotective 37 effect in obese ZSF1 rats.3 38 Introduction 39 Cardiometabolic syndrome (CMS)-a condition that encompasses impaired 40 metabolism (insulin resistance [IR], impaired glucose tolerance), dyslipidemia, hypertension, 41 renal dysfunction, central obesity, and heart failure (HF)-is now recognized as a disease by 42 the World Health Organization (WHO) and the American Society of Endocrinology [1]. 43 Obesity and diabetes mellitus comorbidities are associated with progressive left ventricular 44 (LV) remodeling and dysfunction. Also, these comorbidities are commonly observed in HF 45 with preserved ejection fraction (HFpEF) [2]. Results from a recent epidemiological study 46 (cohort of 3.5 million individuals) demonstrated an incremental increase in the hazard ratio 47 (HR) for HF; HRs were 1.8 in normal weight individuals with three metabolic abnormalities, 48 2.1 in overweight individuals with three metabolic abnormalities, and up to 3.9 in obese 49 individuals with three metabolic abnormalities. Incidence of HFpEF, which currently 50 represents approximately 50% of all HF cases, continues to rise and its prognosis fails to 51 improve partly due to the lack of therapies available to treat this disease [3]. 52 An important step in the development of novel therapeutic agents against CMS is the 53 establishment of a preclinical model that represents a cluster of cardiometabolic disturbances ...

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“…Although many mechanisms of action for the insulin sensitizing actions of metformin have been proposed 4 , few if any of these would explain the beneficial weight loss promoting effects of the drug which continue to be recognised 5 . A recent observational epidemiological study 6 noted a robust association of metformin use with circulating levels of GDF15, a peptide hormone produced by cells responding to a wide range of stressors 7 . GDF15 acts through a receptor complex solely expressed in the hindbrain, through which it suppress food intake [8][9][10][11] .…”

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confidence: 99%

GDF15 and the beneficial actions of metformin in pre-diabetes

Chen

Taskar

et al. 2019

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Metformin, the world's most prescribed anti-diabetic drug, is also effective in preventing Type 2 diabetes in people at high risk, by lowering body weight, fat mass and circulating insulin levels through mechanisms that are incompletely understood.Recent observational studies reporting the association of metformin use and circulating levels of GDF15 led us to hypothesize that GDF15, which signals through a specific receptor complex in the hindbrain to reduce body weight, might mediate these effects. We measured GDF15 in people without diabetes from a randomized placebocontrolled trial of metformin. Over 18 months, participants allocated metformin lost significant weight and levels of GDF15 were persistently elevated compared to placebo.The change in plasma GDF15 in this study correlated positively with weight loss. In wild-type mice, oral metformin increased circulating GDF15 with GDF15 expression increasing predominantly in the distal intestine and the kidney. Metformin prevented weight gain in response to high fat diet in wild-type mice but not in mice lacking GDF15 or its receptor GFRAL. In obese, high fat-fed mice, the effects of metformin to reduce body weight were reversed by a GFRAL antagonist antibody. Metformin had effects on both energy intake and energy expenditure that required GDF15. The insulin sensitising effects of metformin determined by insulin tolerance were abolished in mice lacking GDF15. Metformin significantly reduced fasting glucose and insulin levels in wild type but not in mice lacking GDF15. In summary, metformin increases the circulating levels A.M. is supported by a studentship from the Experimental Medicine Training Initiative/AstraZeneca. R.A.T. and L.

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The MIC-1/GDF15-GFRAL Pathway in Energy Homeostasis: Implications for Obesity, Cachexia, and Other Associated Diseases

Cited by 271 publications

References 167 publications

CXCL5-mediated recruitment of neutrophils into the peritoneal cavity ofGdf15-deficient mice protects against abdominal sepsis

CXCL5-mediated recruitment of neutrophils into the peritoneal cavity ofGdf15-deficient mice protects against abdominal sepsis

The evolving systemic biomarker milieu in obese ZSF1 rat model of human cardiometabolic syndrome: Characterization of the model and cardioprotective effect of GDF15

GDF15 and the beneficial actions of metformin in pre-diabetes

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