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 α-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.
Highlights
Obesity has become an international problem, leading the World Health Organization (WHO) to declare it a global pandemic [1]
To corroborate whether what was found in Drosophila occurs in mammals, we examined the regulation of feeding behavior by simvastatin in the hypothalamus of mice and rats
Using quantitative RT-PCR, we validated that starvation significantly reduced Hmgcr head expression in males (Figure 1C), whereas maintaining the flies on diets containing various concentrations of macronutrients had no significant effect (Figure 1D)
Summary
Obesity has become an international problem, leading the World Health Organization (WHO) to declare it a global pandemic [1]. Even though HMGCR is highly expressed in the brain [13,14], no studies have addressed the specific role of this gene in relation to the central regulation of energy metabolism or BMI maintenance. Only a set of medium-sized neurosecretory cells in the pars intercerebralis (PI) of the brain, called insulin-producing cells (IPCs), produce and secrete the insulin-like peptides (ILPs) DILP2, 3, and 5 [17]. These cells share functional and physiological similarities with the β-cells of the mammalian pancreas. To corroborate whether what was found in Drosophila occurs in mammals, we examined the regulation of feeding behavior by simvastatin in the hypothalamus of mice and rats
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