Screening of Antiobesity Drugs

Introduction & rationale

• Obesity (screening definition) — excessive fat mass from increased adipocyte size (hypertrophy) and/or number (hyperplasia), arising when energy intake exceeds energy expenditure; a multifactorial disease of dysregulated hypothalamic energy homeostasis.
• Why screen — obesity drives type 2 diabetes and its vascular complications, dyslipidaemia, fatty liver, hypertension, several cancers and osteoarthritis — a large comorbidity burden that made animal-model research a major field over the last two decades.
• Two-stage paradigm — the cascade first induces a reproducible obese phenotype in a laboratory species, then quantifies a test article's ability to reduce body weight / adiposity against validated endpoints and a reference anti-obesity standard.
• Species choice — the mouse is the first-line model (routine genetic manipulation, human-similar biology) but no single model reproduces all facets (behaviour + energy expenditure + genetics) of human obesity — a complementary panel is used.
• Physiological substrate — assays interrogate the leptin–hypothalamic axis: adipocyte leptin (proportional to fat mass; stimulated by insulin + glucocorticoids) acts via the leptin receptor (OB-R/Lepr) to balance orexigenic (NPY, AgRP, orexins, MCH, galanin) against anorectic (α-MSH/melanocortin, CRH, CCK, GLP-1, CGRP) neuropeptides; the β₃-adrenoceptor governs rodent lipid/thermogenic metabolism.
• Historical anchor — Hetherington & Ranson (1939) showed electrolytic lesions confined to the ventromedial hypothalamus produce obesity — the founding experimental model; Sclafani's classification is the recognised taxonomy of animal obesity models.