Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

Klein, Anders Bue; Nicolaisen, T; Ørtenblad, Niels; Gejl, Kasper Degn; Jensen, Rasmus; Fritzen, Andreas M.; Larsen, Emil List; Karstoft, Kristian; Poulsen, Henrik Enghusen; Morville, Thomas; Sahl, Ronni Eg; Helge, Jørn Wulff; Lund, J. W.; Falk, Sarah; Lyngbæk, Mark; Ellingsgaard, Helga; Pedersen, Bente Klarlund; Lu, Wei; Finan, Brian; Jørgensen, Sebastian Beck; Seeley, Randy J.; Kleinert, Maximilian; Kiens, Bente; Clemmensen, Christoffer

doi:10.1038/s41467-021-21309-x

Cited by 94 publications

(80 citation statements)

References 32 publications

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“…1g,h). Furthermore, in line with our previous data on normal voluntary wheel running activity of TG mice 17,19 and contrary to recent findings on pharmacological GDF15 treatment 5 , we here show that physical cage activity reflected the regular nocturnal murine activity pattern, and daytime as well as total activity was similar in WT and TG (Fig. 1i,j), supporting the lack of malaise in TG mice.…”

Section: Mainsupporting

confidence: 82%

“…This fits with the well-known actions of the hindbrain AP in the control of nausea and vomiting 11 , beside its role as a control center of food intake 12 . Furthermore, recent data indicate that administration of recombinant GDF15 substantially lowers voluntary wheel running activity in mice 5 . Importantly, all evidence to date for the induction of malaise states through the GDF15-GFRAL pathway utilized supraphysiological doses of exogenously administered GDF15 or acute activation of the GDF15-GFRAL axis.…”

Section: Mainmentioning

confidence: 99%

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Mitochondrial stress-induced GDF15-GFRAL axis promotes anxiety-like behavior and CRH-dependent anorexia

Gil

Coull

Jonás

et al. 2021

Preprint

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Growth differentiation factor 15 (GDF15) is a stress-induced cytokine that modulates food intake and energy metabolism. Until now, most mechanistic studies on GDF15 rely on pharmacological interventions using exogenous GDF15, but little is known about its mode of action when induced both chronically and endogenously. Mitochondrial stress is one of the most described physiological conditions that induces GDF15, and therefore an important model to study the underlying mechanisms of endogenous GDF15 action. Here, using a mouse model of mitochondrial dysfunction via elevated respiratory uncoupling in skeletal muscle, we show a circadian oscillation of muscle-derived GDF15 to promote a daytime-restricted anorexia without signs of nausea or reduced physical activity, contrary to findings using recombinant GDF15. We find that mitochondrial stress-induced GDF15 associates with increased anxiety and hypothalamic corticotropin releasing hormone (CRH) induction, without further activation of the hypothalamic-pituitary-adrenal (HPA) axis and corticosterone response. Strikingly, the daytime-restricted anorexia, lean phenotype, systemic shift in substrate metabolism and anxiety-like behavior are completey abolished in conditions of mitochondrial stress coupled with genetic ablation of the GDF15 receptor GDNF receptor alpha-like (GFRAL), which is predominantly expressed in the hindbrain. Finally, we demonstrate that stress-induced GDF15-GFRAL signaling is required for hypothalamic CRH induction to control diurnal food intake in a CRH-receptor 1 (CRHR1)-dependent manner. With this, we uncover for the first time a molecular target of the GDF15-GFRAL axis that links anxiolytic and anorectic behavior as downstream effects of the chronic activation of this pathway by mitochondrial stress.

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Section: Mainsupporting

confidence: 82%

Section: Mainmentioning

confidence: 99%

Mitochondrial stress-induced GDF15-GFRAL axis promotes anxiety-like behavior and CRH-dependent anorexia

Gil

Coull

Jonás

et al. 2021

Preprint

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“…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). This range of actions would be consistent with GDF15 playing a role in signaling the presence of chemical threats to the organism which might be mitigated by reduced rate of exposure to, or expulsion of, ingested toxins and the promotion of their avoidance in future.…”

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.

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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.

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“…By contrast, administration of GDF15 to rodents reduces food intake and ameliorates glucose tolerance. Interestingly, a recent study reports that high pharmacological doses of GDF15 used in most studies reduce food intake, while physiological induction of endogenous circulating GDF15 levels does not affect it [53]. Although TGFβ receptors were initially reported to mediate the effects of GDF15, the presence of TGFβ contamination in recombinant GDF15 and the lack of a direct binding of GDF15 to known TGFβ receptors led to the search for the bona fide receptor of GDF15.…”

Section: Skeletal Musclementioning

confidence: 99%

The PPARβ/δ-AMPK Connection in the Treatment of Insulin Resistance

Aguilar-Recarte

Palomer

Wahli

et al. 2021

IJMS

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The current treatment options for type 2 diabetes mellitus do not adequately control the disease in many patients. Consequently, there is a need for new drugs to prevent and treat type 2 diabetes mellitus. Among the new potential pharmacological strategies, activators of peroxisome proliferator-activated receptor (PPAR)β/δ show promise. Remarkably, most of the antidiabetic effects of PPARβ/δ agonists involve AMP-activated protein kinase (AMPK) activation. This review summarizes the recent mechanistic insights into the antidiabetic effects of the PPARβ/δ-AMPK pathway, including the upregulation of glucose uptake, muscle remodeling, enhanced fatty acid oxidation, and autophagy, as well as the inhibition of endoplasmic reticulum stress and inflammation. A better understanding of the mechanisms underlying the effects resulting from the PPARβ/δ-AMPK pathway may provide the basis for the development of new therapies in the prevention and treatment of insulin resistance and type 2 diabetes mellitus.

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Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise

Cited by 94 publications

References 32 publications

Mitochondrial stress-induced GDF15-GFRAL axis promotes anxiety-like behavior and CRH-dependent anorexia

Mitochondrial stress-induced GDF15-GFRAL axis promotes anxiety-like behavior and CRH-dependent anorexia

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

The PPARβ/δ-AMPK Connection in the Treatment of Insulin Resistance

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