More than one-third of the worldwide population is overweight or obese and therefore at risk of developing type 2 diabetes mellitus. In order to mitigate this pandemic, safer and more potent therapeutics are urgently required. This necessitates the continued use of animal models to discover, validate and optimize novel therapeutics for their safe use in humans. In order to improve the transition from bench to bedside, researchers must not only carefully select the appropriate model but also draw the right conclusions. In this Review, we consolidate the key information on the currently available animal models of obesity and diabetes and highlight the advantages, limitations and important caveats of each of these models.

(DR) in the sense that MR increases rodent longevity, but without food restriction. We report here that MR also persistently increases total energy expenditure (EE) and limits fat deposition despite increasing weightspecific food consumption. In Fischer 344 (F344) rats consuming control or MR diets for 3, 9, and 20 mo, mean EE was 1.5-fold higher in MR vs. control rats, primarily due to higher EE during the night at all ages. The day-to-night transition produced a twofold higher heat increment of feeding (3.0°C vs. 1.5°C) in MR vs. controls and an exaggerated increase in respiratory quotient (RQ) to values greater than 1, indicative of the interconversion of glucose to lipid by de novo lipogenesis. The simultaneous inhibition of glucose utilization and shift to fat oxidation during the day was also more complete in MR (RQ ϳ0.75) vs. controls (RQ ϳ0.85). Dietary MR produced a rapid and persistent increase in uncoupling protein 1 expression in brown (BAT) and white adipose tissue (WAT) in conjunction with decreased leptin and increased adiponectin levels in serum, suggesting that remodeling of the metabolic and endocrine function of adipose tissue may have an important role in the overall increase in EE. We conclude that the hyperphagic response to dietary MR is matched to a coordinated increase in uncoupled respiration, suggesting the engagement of a nutrient-sensing mechanism, which compensates for limited methionine through integrated effects on energy homeostasis. energy expenditure; metabolic efficiency; oxidative metabolism; futile cycles; adipose tissue; dietary restriction DIETARY METHIONINE RESTRICTION (MR) extends lifespan by 30 -35% in rats (28, 31) and mice (27) by delaying all causes of death. The increase in lifespan is accompanied by a reduction in adiposity that occurs despite a paradoxical increase in weight-specific food consumption (25,28,46). Pair-feeding studies comparing rats fed the control diet to the amount of MR diet consumed by the MR group clearly show that dietary MR decreases metabolic efficiency (25, 46), but the underlying basis for the metabolic responses to dietary MR remains poorly understood. Short-(12 wk) and long-term (80 wk) consumption of the MR diet after weaning also reduced circulating triglyceride, insulin, and leptin while increasing plasma adiponectin (25, 29). Collectively, work to date makes a compelling case that limitation of fat deposition by dietary MR is associated with preservation of insulin sensitivity and significant improvements in metabolic markers of lipid metabolism. Using the tools of metabolic phenotyping to examine energy homeostasis and peripheral substrate utilization, we found that dietary MR produced a significant long-term increase in EE that was temporally linked to exaggerated thermogenic responses to feeding and modest increases in resting EE. These physiological responses to MR limited fat deposition and were associated with significant changes in the metabolic and endocrine function of brown and white adipose tissue. MR effectively increas...