Frontiers in pharmacology · 2026
Diet-induced obesity impairs refeeding responses and downregulates lateral septal GLP-1R in male rats: an effect reversed by weight-loss treatment.
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Covarrubias María José, Dib Tatiana, Escobar-Luna Jorge, Moreno Robinson D, Cáceres-Vergara Daniela, Saldias Cristina, Renard Georgina M, Iturriaga-Vásquez Patricio, Escobar Angélica P, Torres Gonzalo E, Sotomayor-Zárate Ramón
Аннотация
INTRODUCTION: The lateral septum (LS) is a brain area involved in important physiological functions such as reward, stress response, and autonomic regulation. The LS is one of the brain areas with the highest expression of the glucagon-like peptide-1 receptor (GLP-1R), and pharmacological modulation of GLP-1R in the LS affects food intake. However, the relationship between obesity development and LS dysregulation of the GLP-1/GLP-1R system has been poorly studied.
METHODS: We aimed to investigate whether chronic exposure to a high-fat diet (HFD) from weaning to postnatal day (PND) 62 affects the LS GLP-1 system, LS neurotransmitter content, and post-fasting refeeding behavior in rats. Furthermore, we evaluated LS GLP-1R levels and refeeding behavior after pharmacological (phentermine, an amphetamine derivative) and dietary (switch to control diet) interventions.
RESULTS: Our results show that HFD decreases LS GLP-1R protein levels in male rats, while receptor gene expression increases in female rats. Otherwise, chronic exposure to HFD increases LS glutamate content only in female rats. Treatment with phentermine (30 mg/kg/day) and a control diet reduces body weight and fat tissues in obese rats of both sexes. However, in these animals, the re-exposure to fasting resulted in a marked preference for consuming HFD, an effect not observed in obese rats only exposed to a control diet. Finally, LS GLP-1R levels were normalized in obese male rats treated with phentermine plus a control diet or only with a control diet.
CONCLUSION: In conclusion, the chronic exposure to HFD induces sex differences in LS that could be related to pathological mechanisms observed in obesity and to the efficacy of treatment with GLP-1R agonists. Moreover, phentermine, a classic anorectic drug used for short-term weight loss, generates neurobiological adaptations that increase fasting-induced caloric intake, which could be related to the weight regain observed in obese patients.
METHODS: We aimed to investigate whether chronic exposure to a high-fat diet (HFD) from weaning to postnatal day (PND) 62 affects the LS GLP-1 system, LS neurotransmitter content, and post-fasting refeeding behavior in rats. Furthermore, we evaluated LS GLP-1R levels and refeeding behavior after pharmacological (phentermine, an amphetamine derivative) and dietary (switch to control diet) interventions.
RESULTS: Our results show that HFD decreases LS GLP-1R protein levels in male rats, while receptor gene expression increases in female rats. Otherwise, chronic exposure to HFD increases LS glutamate content only in female rats. Treatment with phentermine (30 mg/kg/day) and a control diet reduces body weight and fat tissues in obese rats of both sexes. However, in these animals, the re-exposure to fasting resulted in a marked preference for consuming HFD, an effect not observed in obese rats only exposed to a control diet. Finally, LS GLP-1R levels were normalized in obese male rats treated with phentermine plus a control diet or only with a control diet.
CONCLUSION: In conclusion, the chronic exposure to HFD induces sex differences in LS that could be related to pathological mechanisms observed in obesity and to the efficacy of treatment with GLP-1R agonists. Moreover, phentermine, a classic anorectic drug used for short-term weight loss, generates neurobiological adaptations that increase fasting-induced caloric intake, which could be related to the weight regain observed in obese patients.