A Novel Rodent Model That Mimics the Metabolic Sequelae of Obese Craniopharyngioma Patients

Abstract

Patients with craniopharyngioma (CP), a tumor located in the pituitary and/or hypothalamus, are susceptible to developing obesity and many metabolic complications. The study aim was to create a rodent model that mimics the complex neuroanatomical and metabolic disturbances commonly seen in obese CP patients. We compared the metabolic phenotype of animals with three distinct types of hypothalamic lesions: 1) destruction of the arcuate nucleus (ARC) induced by monosodium glutamate (MSG), 2) electrolytic lesion of the adjacent ventromedial nucleus (VMN) alone, 3) both the VMN and dorsomedial nucleus (DMN), or a 4) combined medial hypothalamic lesion (CMHL) affecting the VMN, DMN, and the ARC. Only the CMHL model exhibited all key features observed in patients with hypothalamic obesity induced by CP. These features included excessive weight gain due to increased adiposity, increased food intake, and pronounced hyperinsulinemia and hyperleptinemia. Similar to characteristics of patients with CP, CMHL animals exhibited reduced plasma levels of alpha-melanocyte stimulating hormone and reduced ambulatory activity compared with weight-matched controls. Therefore, the CMHL model best mimics the complex metabolic abnormalities observed in obese CP patients compared with lesions to other hypothalamic areas and provides a foundation for future pharmacological approaches to treat obesity in children with hypothalamic damage.

Glucagon-Like Peptide-1 Agonist Exendin-4 Leads to Reduction of Weight and Caloric Intake in a Rat Model of Hypothalamic Obesity

“…An immediate increase in FI resulted in a significantly increased BW 1 day after surgery in the CMHL group. At the time of Ex4 treatment (6 weeks after surgery), FI in lesioned rats dropped to the amount of control rats (CMHL 97.6 ± 6.2 kcal/day, control 93.6 ± 3.9 kcal/day metabolizable energy; p = 0.581), similar to our previous studies [22]. …”

“…In the current study, we tested Ex4 in our CMHL rat model mimicking metabolic disturbances typically observed in patients with HO. In this model of CMHLs [22], Ex4 injections resulted in significant reduction of FI and an attenuation of weight gain.…”

“…These hypothalamic nuclei are targets for anti-obesity drugs such as sibutramine that may require intact hypothalamic signaling pathways for appetite inhibition. Patients with HO secondary to CP frequently have damaged medial hypothalamic nuclei and consequently aberrant hypothalamic signaling pathways [3,22]. In one pediatric study utilizing sibutramine, which requires intact hypothalamic signaling pathways, significant weight loss occurred in patients with HO although it was less pronounced than in patients with uncomplicated obesity [15].…”

“…The upper incisor bar was 3.5 mm above the interaural line. Lesions were targeted to the ARC, VMN, and DMN through the placement of an insulated stainless steel electrode at stereotaxic coordinates based on our previous study [22]. Specifically, an anodal electric current (110 V, 1.7 mA for 15 s) was passed through the tip of the electrode while placed 2.6 mm posterior to the bregma, 0.5 mm lateral to the midsagittal line, and both 10 mm (ARC) and 8.6 mm (VMN/DMN) ventral from the skull.…”

“…We recently developed a novel combined medial hypothalamic lesion (CMHL) model that utilizes electrolytic lesions in the ARC, VMG, and DMN of the medial hypothalamus to model the sequelae commonly observed in HO secondary following the resection and/or radiotherapy of CP [22]. We found similar results when combining electrolytic lesions of the VMN with chemical lesions of the ARC [17].…”