Growth Differentiation Factor-15 (GDF-15) Inhibits Gastric Emptying in Rodents as Part of Its Anorectic Mechanism of Action

Hinke, Simon A.; Cavanaugh, Cassandre R.; Kirchner, Thomas; Lang, Wensheng; Meng, Rong; Wallace, Nathaniel; Liu, Jr. Jianying; D’Aquino, Katharine; Ho, George; Rankin, Matthew M.; Wang, Shengping; Chavez, Jose A.; Nelson, Serena; Furman, Jennifer L.; Mullican, Shannon E.; Rangwala, Shamina M.; Nawrocki, Andrea R.

doi:10.2337/db18-283-lb

Cited by 3 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recombinant GDF15 or extended half-life GDF15 molecules have been administered in multiple models of obesity in mice, rats, and monkeys [ 24 , 25 , 28 , 56 , 84 , 85 ]. In all the preclinical models studied, administration of various GDF15 molecules consistently resulted in decreased food intake and body weight.…”

Section: Gdf15 For Treating Obesitymentioning

confidence: 99%

Growth differentiation factor 15 as a potential therapeutic for treating obesity

Hale

Véniant

2021

Molecular Metabolism

View full text Add to dashboard Cite

Background Obesity is rapidly becoming one of the world's most critical health care concerns. Comorbidities accompanying excess weight include cardiovascular disease, diabetes, and certain cancers. These comorbidities result in greater hospitalization and other health care-related costs. Economic impacts are likely to be felt more acutely in developing countries, where obesity rates continue to rise and health care resources are already insufficient. Some of the more effective treatments are invasive and expensive surgeries, which some economies in the world cannot afford to offer to a broad population. Pharmacological therapies are needed to supplement treatment options for patients who cannot, or will not, undergo surgical treatment. However, the few drug therapies currently available have either limited efficacy or safety concerns. A possible exception has been glucagon-like peptide-1 analogs, although these have shown a number of adverse events. New drug therapies that are safe and produce robust weight loss are needed. Scope of review Herein, we review the role of growth differentiation factor 15 (GDF15) in feeding behavior and obesity, summarize some of the new and exciting biological discoveries around signaling pathways and tissue sites of action, and highlight initial efforts to develop GDF15-based therapies suitable for inducing weight loss in humans. Major conclusions Within the last several years, great strides have been made in understanding the biology of GDF15. Recent developments include identification of an endogenous receptor, biological localization of the receptor system, impact on energy homeostasis, and identification of molecules suitable for administration to humans as anti-obesity treatments. New and exciting research on GDF15 suggests that it holds promise as a novel obesity treatment as new molecules progress toward clinical development.

show abstract

Section: Gdf15 For Treating Obesitymentioning

confidence: 99%

Growth differentiation factor 15 as a potential therapeutic for treating obesity

Hale

Véniant

2021

Molecular Metabolism

View full text Add to dashboard Cite

show abstract

“…GDF15 signals via a heterodimeric receptor, GDNF-family receptor α-like (GFRAL)-RET, localized specifically in the brainstem (14)(15)(16)(17). To date, reports of the central actions of GDF15 in mammals have largely focused on regulation of food intake anorexia, weight loss (18)(19)(20), emesis (21), pica (22), delayed gastric emptying (23,24), and conditioned aversion (25). Recent data indicate that GDF15 administration also reduces physical activity in mice (26).…”

mentioning

confidence: 99%

Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15

Cimino

Kim

Tung

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic–pituitary–adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15−/− mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.

show abstract

“…Especially, GDF15, which is also induced by the UPR 38 and expressed in high levels by adipose tissue macrophages, 39 has been the focus of recent investigations for its capacity to regulate body weight. Via signaling through GFRAL (GDNF [glial-derived neurotrophic factor] receptor alpha-like) receptor-expressing neurons in the hindbrain GDF15 reduces gastric emptying, 40 induces taste aversion, 41 and reduces food intake, [40][41][42] which could explain the altered feeding pattern we observe upon ONX-0914 treatment. Furthermore, GDF15 was reported to enhance lipolysis and thermogenesis without a significant reduction in food intake through activation of the sympathetic nervous system, 39 which could also have contributed to ONX-0914mediated reduction in body weight.…”

Section: Discussionmentioning

confidence: 92%

“…To find an explanation for the observed metabolic phenotype, we consulted literature for an ER stress–inducible cytokine with weight-lowering effects. As GDF15 (growth differentiation factor 15) fits this description and is produced by adipose tissue macrophages (among other cell types) and has also immunoinhibitory effects, 38–44 we assessed the GDF15 levels in the atherosclerosis initiation study (female LDLr −/− fed a WTD and treated for 7 weeks), preexisting adipose tissue study (male LDLr −/− mice on a WTD for 11 weeks and treated the last 7 weeks), and short-term treatment study (male LDLr −/− on a WTD for 5 weeks, treated for 1 day or 1 week). ONX-0914 treatment upregulated blood plasma GDF15 concentrations in all of these studies (Figure S16A through S16C).…”

Section: Resultsmentioning

confidence: 99%

Immunoproteasomal Inhibition With ONX-0914 Attenuates Atherosclerosis and Reduces White Adipose Tissue Mass and Metabolic Syndrome in Mice

Schaftenaar,

van Dam,

de Bruin

et al. 2024

ATVB

View full text Add to dashboard Cite

BACKGROUND: Atherosclerosis is the major underlying pathology of cardiovascular disease and is driven by dyslipidemia and inflammation. Inhibition of the immunoproteasome, a proteasome variant that is predominantly expressed by immune cells and plays an important role in antigen presentation, has been shown to have immunosuppressive effects. METHODS: We assessed the effect of ONX-0914, an inhibitor of the immunoproteasomal catalytic subunits LMP7 (proteasome subunit β5i/large multifunctional peptidase 7) and LMP2 (proteasome subunit β1i/large multifunctional peptidase 2), on atherosclerosis and metabolism in LDLr –/– and APOE*3-Leiden.CETP mice. RESULTS: ONX-0914 treatment significantly reduced atherosclerosis, reduced dendritic cell and macrophage levels and their activation, as well as the levels of antigen-experienced T cells during early plaque formation, and Th1 cells in advanced atherosclerosis in young and aged mice in various immune compartments. Additionally, ONX-0914 treatment led to a strong reduction in white adipose tissue mass and adipocyte progenitors, which coincided with neutrophil and macrophage accumulation in white adipose tissue. ONX-0914 reduced intestinal triglyceride uptake and gastric emptying, likely contributing to the reduction in white adipose tissue mass, as ONX-0914 did not increase energy expenditure or reduce total food intake. Concomitant with the reduction in white adipose tissue mass upon ONX-0914 treatment, we observed improvements in markers of metabolic syndrome, including lowered plasma triglyceride levels, insulin levels, and fasting blood glucose. CONCLUSIONS: We propose that immunoproteasomal inhibition reduces 3 major causes underlying cardiovascular disease, dyslipidemia, metabolic syndrome, and inflammation and is a new target in drug development for atherosclerosis treatment.

show abstract

Growth Differentiation Factor-15 (GDF-15) Inhibits Gastric Emptying in Rodents as Part of Its Anorectic Mechanism of Action

Cited by 3 publications

References 0 publications

Growth differentiation factor 15 as a potential therapeutic for treating obesity

Growth differentiation factor 15 as a potential therapeutic for treating obesity

Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15

Immunoproteasomal Inhibition With ONX-0914 Attenuates Atherosclerosis and Reduces White Adipose Tissue Mass and Metabolic Syndrome in Mice

Contact Info

Product

Resources

About