Abstract

The statin drug target, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), is strongly linked to body mass index (BMI), yet how HMGCR influences BMI is not understood. In mammals, studies of peripheral HMGCR have not clearly identified a role in BMI maintenance and, despite considerable central nervous system expression, a function for central HMGCR has not been determined. Similar to mammals, Hmgcr is highly expressed in the Drosophila melanogaster brain. Therefore, genetic and pharmacological studies were performed to identify how central Hmgcr regulates Drosophila energy metabolism and feeding behavior. We found that inhibiting Hmgcr, in insulin-producing cells of the Drosophila pars intercerebralis (PI), the fly hypothalamic equivalent, significantly reduces the expression of insulin-like peptides, severely decreasing insulin signaling. In fact, reducing Hmgcr expression throughout development causes decreased body size, increased lipid storage, hyperglycemia, and hyperphagia. Furthermore, the Hmgcr induced hyperphagia phenotype requires a conserved insulin-regulated alpha-glucosidase, target of brain insulin (tobi). In rats and mice, acute inhibition of hypothalamic Hmgcr activity stimulates food intake. This study presents evidence of how central Hmgcr regulation of metabolism and food intake could influence BMI.

Keywords

body maintenance index; obesity; statins; mevalonate pathway; metabolism; feeding behavior; hypothalamus

Published in

Cells
2022, Volume: 11, number: 6, article number: 970
Publisher: MDPI

SLU Authors

• Khan, Zaid

  • Department of Plant Protection Biology, Swedish University of Agricultural Sciences
    
  • Uppsala University

UKÄ Subject classification

Cell Biology


Publication identifier

DOI: https://doi.org/10.3390/cells11060970

Permanent link to this page (URI)

https://res.slu.se/id/publ/116721