GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis

Brain Behav Immun. 2025 Feb:124:280-293. doi: 10.1016/j.bbi.2024.12.010. Epub 2024 Dec 11.

Abstract

Weight loss is a common early sign in amyotrophic lateral sclerosis (ALS) patients and negatively correlates with survival. In different cancers and metabolic disorders, high levels of serum growth differentiation factor 15 (GDF15) contribute to a decrease of food intake and body weight, acting through GDNF family receptor alpha-like (GFRAL). Here we report that GDF15 is highly expressed in the peripheral blood of ALS patients and in the hSOD1G93A mouse model and that GFRAL is upregulated in the brainstem of hSOD1G93A mice. We demonstrate that the localized GFRAL silencing by shRNA in the area postrema/nucleus tractus solitarius of hSOD1G93A mice induces weight gain, reduces adipose tissue wasting, ameliorates the motor function and muscle atrophy and prolongs the survival time. We report that microglial cells could be involved in mediating these effects because their depletion with PLX5622 reduces brainstem GDF15 expression, weight loss and the expression of lipolytic genes in adipose tissue. Altogether these results reveal a key role of GDF15-GFRAL signaling in regulating weight loss and the alteration of and lipid metabolism in the early phases of ALS.

Keywords: Adipose tissue; Feeding behaviour; GDF15; GFRAL; Microglia; Neurodegenerative disease.

MeSH terms

  • Adipose Tissue / metabolism
  • Amyotrophic Lateral Sclerosis* / genetics
  • Amyotrophic Lateral Sclerosis* / metabolism
  • Animals
  • Brain Stem / metabolism
  • Disease Models, Animal*
  • Female
  • Glial Cell Line-Derived Neurotrophic Factor Receptors* / genetics
  • Glial Cell Line-Derived Neurotrophic Factor Receptors* / metabolism
  • Growth Differentiation Factor 15* / genetics
  • Growth Differentiation Factor 15* / metabolism
  • Humans
  • Lipid Metabolism* / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / metabolism
  • Muscular Atrophy / metabolism
  • Signal Transduction*
  • Weight Loss*

Substances

  • Growth Differentiation Factor 15
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • GFRAL protein, mouse
  • Gdf15 protein, mouse