Efavirenz increased ghrelin levels and upregulated ghrelin and NPY receptors in the hypothalamus, driving increased appetite and sucrose preference in mice — yet paradoxically caused weight loss despite greater food intake.
Ghrelin & NPY receptors upregulatedEfavirenz increased both ghrelin levels and the expression of its receptor (GHS-R1a) plus neuropeptide Y receptor 1 in the hypothalamus — a double hit on the brain's hunger circuit
What the researchers found
After 36 days of efavirenz (10 mg/kg oral) in CD1 mice:
- **Appetite signaling increased**: Serum ghrelin rose, and hypothalamic expression of GHS-R1a (ghrelin receptor) and NPYR1 (neuropeptide Y receptor 1) were upregulated.
- **Eating behavior changed**: Food intake increased and sucrose preference was elevated, consistent with enhanced reward-driven eating.
- **Paradoxical weight loss**: Despite eating more, mice in the efavirenz group lost weight.
- **Metabolic disruption**: Triglycerides and cholesterol increased.
- **Leptin findings**: Serum leptin, soluble leptin receptor (sOB-R), and free leptin index showed that the increased hunger was not caused by reduced satiety signaling — rather, hunger was independently stimulated through the ghrelin/NPY axis.
Why it matters
Over 39 million people worldwide live with HIV, and most take antiretroviral drugs long-term. Metabolic side effects — including obesity, dyslipidemia, and insulin resistance — are major quality-of-life concerns. Understanding exactly how these drugs alter peptide hormone signaling in the brain's appetite centers could lead to targeted interventions (such as ghrelin antagonists or NPY modulators) to manage these side effects.
How the study worked
CD1 mice received efavirenz (10 mg/kg) or distilled water (control) orally for 36 days. Measurements included body weight and food intake throughout treatment, metabolic panels (glucose, triglycerides, cholesterol), serum peptide hormones (leptin, sOB-R, ghrelin), hypothalamic receptor expression (GHS-R1a, NPYR1, leptin) via immunohistochemistry or similar techniques, and a sucrose preference test.
What this study cannot tell us
The study was conducted in mice, and efavirenz metabolism may differ from humans. Only male mice were studied. The paradoxical weight loss despite increased intake wasn't mechanistically explained — energy expenditure was not directly measured. The 36-day treatment period may not capture long-term metabolic adaptations. The dose used (10 mg/kg) may not directly translate to human therapeutic doses.
How to read the evidence
This is a preclinical study in mice with a single drug dose level and relatively small sample. While the findings are novel and the experimental design is sound, they require replication and human validation.
When this study was published
Published in 2026, this is a very recent study addressing an underexplored aspect of antiretroviral drug side effects — their impact on neuropeptide-driven appetite circuits.
The bigger picture
This study adds to growing evidence that drugs affecting brain reward and appetite circuits do so through specific neuropeptide pathways — ghrelin and NPY in this case. It also highlights that weight changes during drug treatment can't be explained by appetite alone; energy expenditure and metabolic partitioning (where calories go) are equally important. The paradoxical finding of increased appetite with weight loss suggests efavirenz may also increase energy expenditure, a mechanism that warrants further investigation.
Questions still open
- Does efavirenz similarly upregulate ghrelin and NPY signaling in the brains of HIV patients, and does this drive the metabolic changes seen clinically?
- Could ghrelin receptor antagonists mitigate the appetite-stimulating side effects of antiretroviral drugs?
- What mechanism explains the paradoxical weight loss — is efavirenz increasing energy expenditure or altering nutrient absorption?
Common questions
Why would an HIV drug affect appetite hormones in the brain?
Why did the mice lose weight even though they ate more?
Read the original research
Efavirenz Interacts with Hormones Involved in Appetite and Satiety, Affecting Body Weight in Mice.
International journal of molecular sciences, 27(2)
Citation
Rojas-Osornio, Sandra Angélica; Manuel-Apolinar, Leticia; Crespo-Ramírez, Minerva; Paredes-Cervantes, Vladimir; Mata-Marín, Antonio; Molina-López, José; Pérez de la Mora, Miguel; Borroto-Escuela, Dasiel; Martínez-Lara, Ricardo; Tesoro-Cruz, Emiliano. (2026). Efavirenz Interacts with Hormones Involved in Appetite and Satiety, Affecting Body Weight in Mice.. International journal of molecular sciences, 27(2). https://doi.org/10.3390/ijms27020735