Obesity & Metabolic Disease — Animal Models & Behavioral Testing

Both are leptin pathway models but target different nodes. ob/ob mice lack leptin itself — they produce no functional leptin protein, so exogenous leptin administration completely reverses their obesity. db/db mice lack a functional leptin receptor, so they have extremely high circulating leptin but cannot respond to it. db/db mice develop more severe type 2 diabetes with progressive beta-cell failure, while ob/ob mice on C57BL/6J background show transient hyperglycemia that improves with age.

C57BL/6J mice are uniquely susceptible to diet-induced obesity due to a natural deletion in the nicotinamide nucleotide transhydrogenase (Nnt) gene, which impairs mitochondrial energy metabolism and glucose-stimulated insulin secretion. When placed on a 60% high-fat diet, they reliably develop obesity, insulin resistance, and hepatic steatosis over 12–16 weeks. Other C57BL/6 substrains (e.g., C57BL/6N) have an intact Nnt gene and show different metabolic responses, so substrain matters.

On a 60% kcal high-fat diet, C57BL/6J mice show significant weight divergence from chow-fed controls within 4–6 weeks. A robust obese phenotype with insulin resistance and glucose intolerance is typically established by 12–16 weeks on diet. For maximal metabolic dysfunction including hepatic steatosis and dyslipidemia, 16–20 weeks on diet is recommended. Some researchers use DIO mice commercially available from JAX (pre-fed on HFD for 6+ weeks) to reduce in-house diet exposure time.

Start with the open field test to establish baseline locomotor activity, as obesity profoundly affects ambulation. Follow with cognitive tests (Y-maze, novel object recognition) to assess obesity-driven cognitive decline. Include the elevated plus maze for anxiety-like behavior and forced swim test for depressive-like behavior, as metabolic-psychiatric comorbidity is a key translational outcome. For diabetic models (db/db), add grip strength testing to assess peripheral neuropathy.

Yes, and they are critical to address. Reduced locomotor activity in obese mice can confound any test where movement is the measured outcome — for example, reduced exploration in the elevated plus maze may reflect physical limitation rather than anxiety. Normalize anxiety and cognitive measures for total locomotor output. Use the open field as a covariate. For rotarod, body weight is a major confound; report both latency to fall and body-weight-adjusted performance.

MC4R (melanocortin-4 receptor) knockout mice model the most common single-gene cause of severe obesity in humans. MC4R mutations account for 2–6% of severe early-onset obesity cases in humans. The mice develop progressive, maturity-onset obesity with hyperphagia, hyperinsulinemia, and increased linear growth. Unlike leptin pathway models, MC4R KO mice have intact leptin production and signaling upstream of the melanocortin system, making them the primary model for melanocortin-targeted therapeutics like setmelanotide.

Yes, and this is a rapidly growing research area. High-fat diet and genetic obesity models both develop hippocampal neuroinflammation, characterized by microglial activation, elevated IL-1beta and TNF-alpha, and impaired synaptic plasticity (reduced LTP). Cognitive deficits on NOR and Y-maze correlate with hippocampal neuroinflammatory markers. DIO in C57BL/6J is the most commonly used model for obesity-cognition studies because it recapitulates the diet-driven inflammation relevant to human metabolic cognitive impairment.