Screening of Antiobesity Drugs

Screening of Antiobesity Drugs

1. Definition, scope & rationale of anti-obesity drug screening

• Obesity is defined operationally for screening as an excessive development of fat mass resulting from increased adipocyte size (hypertrophy) and/or increased adipocyte number (hyperplasia), arising when energy intake exceeds energy expenditure (SK Gupta Ch.9, p.152).
• It is a multifactorial disease driven by interaction of behavioural, environmental and genetic factors, with dysregulation of energy homeostasis normally maintained by the hypothalamic neuroendocrine/neurotransmitter network (SK Gupta Ch.9, p.152).
• Obesity is a screening target because of its comorbidities — type 2 diabetes and its macro-/microvascular late complications (stroke, cardiac infarction, peripheral occlusive disease; nephropathy, retinopathy, neuropathy), dyslipidaemia, fatty liver, hypertension, certain cancers and osteoarthritis (Vogel V4 P.XIII, pp.3287–3288; SK Gupta Ch.9, p.152).
• The purpose of the screening cascade is to (1) induce a reproducible obese phenotype in a laboratory species, then (2) quantify a test article's ability to reduce body weight / adiposity against validated endpoints and a reference anti-obesity standard (Vogel V4 P.XIII, pp.3287–3319).
• Central paradigm: research on animal models of obesity became a major field over the last two decades because worldwide obesity incidence rose and its comorbidity burden grew (Vogel V4 P.XIII, p.3287).
• Historical anchor — CNS/hypothalamic influence on obesity was suspected from early clinical observations (Babinski 1900; Fröhlich 1901; Biedl 1916); Hetherington & Ranson (1939) showed electrolytic lesions restricted to the ventromedial hypothalamus produce obesity — the founding experimental model (Vogel V4 P.XIII, p.3287).
• Species choice principle — the mouse is an "ideal" first-line model because it shares broadly similar genetics/development with humans and its genetic-manipulation techniques are routine; but no single animal model reproduces all facets (behaviour + energy expenditure + genetics) of human obesity, so a panel of complementary models is used (SK Gupta Ch.9, pp.165–166).

1.1 Physiological substrate the assays interrogate (why these endpoints)

• Leptin–hypothalamic axis: leptin is synthesised and secreted primarily from adipocytes and acts centrally in the hypothalamus via the leptin receptor (OB-R / Lepr); circulating leptin correlates with body-fat mass; insulin and glucocorticoids stimulate adipocyte leptin production (SK Gupta Ch.9, p.152).
• Low leptin + insulin (fasting/weight loss) → ↑ food intake and ↓ energy expenditure by stimulating neuropeptide Y (NPY) synthesis and inhibiting sympathetic/catabolic pathways; high leptin + insulin (feeding/weight gain) → ↓ food intake and ↑ energy expenditure via melanocortin and corticotropin-releasing hormone (CRH) release (SK Gupta Ch.9, p.152).
• Orexigenic vs anorectic neuropeptides (screening biomarkers; SK Gupta Ch.9, Table 9.1, p.153):
  • Orexigenic (appetite-stimulating): Neuropeptide Y (NPY), Agouti-related peptide (AgRP), Orexins A & B, Galanin, β-endorphin, Norepinephrine, Growth-hormone-releasing hormone, Melanin-concentrating hormone (MCH).
  • Anorectic (appetite-suppressing): CRH, Melanocyte-stimulating hormone (α-MSH), Cholecystokinin (CCK), Glucagon-like peptide-1 (GLP-1), Calcitonin-gene-related peptide (CGRP), Bombesin.
• β₃-adrenoceptor has an important role in the regulation of lipid metabolism and obesity in rodents (target for thermogenic anti-obesity agents), though its physiological function in humans is not yet established (SK Gupta Ch.9, p.152).