Adiponectin overexpression improves metabolic abnormalities caused by acid ceramidase deficiency but does not prolong lifespan in a mouse model of Farber Disease

Marie K Norris; Trevor S Tippetts; Joseph L Wilkerson; Rebekah J Nicholson; J Alan Maschek; Thierry Levade; Jeffrey A Medin; Scott A Summers; William L Holland

doi:10.1016/j.ymgmr.2024.101077

Adiponectin overexpression improves metabolic abnormalities caused by acid ceramidase deficiency but does not prolong lifespan in a mouse model of Farber Disease

Mol Genet Metab Rep. 2024 Apr 3:39:101077. doi: 10.1016/j.ymgmr.2024.101077. eCollection 2024 Jun.

Authors

Marie K Norris^{1

2}, Trevor S Tippetts^{1

2

3}, Joseph L Wilkerson^{1

2}, Rebekah J Nicholson^{1

2}, J Alan Maschek⁴, Thierry Levade⁵, Jeffrey A Medin⁶, Scott A Summers^{1

2}, William L Holland^{1

2}

Affiliations

¹ Department of Nutrition and Integrative Physiology, University of Utah College of Health, Salt Lake City, UT, USA.
² Diabetes and Metabolism Research Center, University of Utah College of Medicine, Salt Lake City, UT, USA.
³ Children's Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁴ Metabolomics Core Facility, University of Utah, Salt Lake City, UT, USA.
⁵ Laboratoire de Biochimie Métabolique, CHU Toulouse and INSERM U1037, Centre de Recherches en Cancérologie de Toulouse, Université Paul Sabatier, 31037 Toulouse, France.
⁶ Departments of Pediatrics and Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.

Abstract

Farber Disease is a debilitating and lethal childhood disease of ceramide accumulation caused by acid ceramidase deficiency. The potent induction of a ligand-gated neutral ceramidase activity promoted by adiponectin may provide sufficient lowering of ceramides to allow for the treatment of Farber Disease. In vitro, adiponectin or adiponectin receptor agonist treatments lowered total ceramide concentrations in human fibroblasts from a patient with Farber Disease. However, adiponectin overexpression in a Farber Disease mouse model did not improve lifespan or immune infiltration. Intriguingly, mice heterozygous for the Farber Disease mutation were more prone to glucose intolerance and insulin resistance when fed a high-fat diet, and adiponectin overexpression protected from these metabolic perturbations. These studies suggest that adiponectin evokes a ceramidase activity that is not reliant on the functional expression of acid ceramidase, but indicates that additional strategies are required to ameliorate outcomes of Farber Disease.

Keywords: Adiponectin; Ceramidase; Ceramide; Farber Disease; Lipotoxicity.