A Leptin Receptor Antagonist Attenuates Adipose Tissue Browning and Muscle Wasting in Infantile Nephropathic Cystinosis-Associated Cachexia

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 8; p. 1954
• Main Authors: Gonzalez, Alex, Cheung, Wai W, Perens, Elliot A, Oliveira, Eduardo A, Gertler, Arieh, Mak, Robert H
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31-07-2021; MDPI
• Subjects: Adipocytes; Adipose tissue; adipose tissue browning; Adipose Tissue, Brown - drug effects; Adipose Tissue, Brown - metabolism; Adipose Tissue, Brown - pathology; Adipose Tissue, White - drug effects; Adipose Tissue, White - metabolism; Adipose Tissue, White - pathology; Amino Acid Transport Systems, Neutral - genetics; Amino Acid Transport Systems, Neutral - metabolism; Animals; Atrophy; Body composition; Body Composition - drug effects; Body fat; Body weight gain; Cachexia; Cachexia - etiology; Cachexia - metabolism; Cachexia - pathology; Cachexia - prevention & control; Cystinosis; Cystinosis - complications; Cystinosis - drug therapy; Cystinosis - metabolism; Cystinosis - pathology; Data analysis; Disease Models, Animal; Energy; Energy balance; Energy expenditure; Food intake; Gene expression; Homeostasis; Hormone Antagonists - pharmacology; infantile nephropathic cystinosis; Kidney diseases; leptin; Lipolysis; Male; Metabolic rate; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle function; muscle wasting; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy - etiology; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Muscular Atrophy - prevention & control; Mutation; Myogenesis; Phenotypes; Proteins; Receptors, Leptin - antagonists & inhibitors; Receptors, Leptin - metabolism; Signal Transduction; Software; United States > US; infantile nephropathic cystinosis; leptin; muscle wasting; adipose tissue browning; cachexia
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10081954

Mice lacking the functional cystinosin gene (
), a model of infantile nephropathic cystinosis (INC), exhibit the cachexia phenotype with adipose tissue browning and muscle wasting. Elevated leptin signaling is an important cause of chronic kidney disease-associated cachexia. The pegylated leptin receptor antagonist (PLA) binds to but does not activate the leptin receptor. We tested the efficacy of this PLA in
mice. We treated 12-month-old
mice and control mice with PLA (7 mg/kg/day, IP) or saline as a vehicle for 28 days. PLA normalized food intake and weight gain, increased fat and lean mass, decreased metabolic rate and improved muscle function. It also attenuated perturbations of energy homeostasis in adipose tissue and muscle in
mice. PLA attenuated adipose tissue browning in
mice. PLA increased gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in
mice. This was accompanied by correcting the increased expression of muscle wasting signaling while promoting the decreased expression of myogenesis in gastrocnemius of
mice. PLA attenuated aberrant expressed muscle genes that have been associated with muscle atrophy, increased energy expenditure and lipolysis in
mice. Leptin antagonism may represent a viable therapeutic strategy for adipose tissue browning and muscle wasting in INC.