Targeting Clic1 for the treatment of obesity: A novel therapeutic strategy to reduce food intake and body weight

  • Mol Metab. 2023 Oct:76:101794. doi: 10.1016/j.molmet.2023.101794.
Rizaldy C Zapata  1 ,  Dinghong Zhang  1 ,  Dongmin Yoon  1 ,  Chanond A Nasamran  2 ,  Daisy R Chilin-Fuentes  2 ,  Avraham Libster  1 ,  Besma S Chaudry  1 ,  Mariela Lopez-Valencia  1 ,  Devasena Ponnalagu  3 ,  Harpreet Singh  3 ,  Michael Petrascheck  4 ,  Olivia Osborn  5
Affiliations
  • 1. Division of Endocrinology and Metabolism, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA.
  • 2. Center for Computational Biology & Bioinformatics, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
  • 3. Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.
  • 4. Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA; Department of Neuroscience, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
  • 5. Division of Endocrinology and Metabolism, School of Medicine, University of California San Diego, La Jolla, CA, 92093, USA. Electronic address: [email protected].
PMID: 37604246 DOI: 10.1016/j.molmet.2023.101794
Abstract

Objective: Despite great advances in obesity therapeutics in recent years, there is still a need to identify additional therapeutic targets for the treatment of this disease. We previously discovered a signature of genes, including Chloride intracellular channel 1 (Clic1), whose expression was associated with drug-induced weight gain, and in these studies, we assess the effect of Clic1 inhibition on food intake and body weight in mice.

Methods: We studied the impact of Clic1 inhibition in mouse models of binge-eating, diet-induced obese mice and genetic models of obesity (Magel2 KO mice).

Results: Clic1 knockout (KO) mice ate significantly less and had a lower body weight than WT littermates when either fed chow or high fat diet. Furthermore, pharmacological inhibition of Clic1 in diet-induced obese mice resulted in suppression of food intake and promoted highly efficacious weight loss. Clic1 inhibition also reduced food intake in binge-eating models and hyperphagic Magel2 KO mice. We observed that chronic obesity resulted in a significant change in subcellular localization of Clic1 with an increased ratio of Clic1 in the membrane in the obese state. These observations provide a novel therapeutic strategy to block Clic1 translocation as a potential mechanism to reduce food intake and lower body weight.

Conclusions: These studies attribute a novel role of Clic1 as a driver of food intake and overconsumption. In summary, we have identified hypothalamic expression of Clic1 plays a key role in food intake, providing a novel therapeutic target to treat overconsumption that is the root cause of modern obesity.

Keywords
Body weight regulation; Clic1; Food intake; Hyperphagia; Obesity.
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