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...

The transcriptional co-activator PGC-1␣ regulates functional plasticity in adipose tissue by linking sympathetic input to the transcriptional program of adaptive thermogenesis. We report here a novel truncated form of PGC-1␣ (NT-PGC-1␣) produced by alternative 3 splicing that introduces an in-frame stop codon into PGC-1␣ mRNA. The expressed protein includes the first 267 amino acids of PGC-1␣ and 3 additional amino acids from the splicing insert. NT-PGC-1␣ contains the transactivation and nuclear receptor interaction domains but is missing key domains involved in nuclear localization, interaction with other transcription factors, and protein degradation. Expression and subcellular localization of NT-PGC-1␣ are dynamically regulated in the context of physiological signals that regulate fulllength PGC-1␣, but the truncated domain structure conveys unique properties with respect to protein-protein interactions, protein stability, and recruitment to target gene promoters. Therefore, NT-PGC-1␣ is a co-expressed, previously unrecognized form of PGC-1␣ with functions that are both unique from and complementary to PGC-1␣.

Nutrient homeostasis is known to be regulated by pancreatic islet tissue. The function of islet ␤-cells is controlled by a glucose sensor that operates at physiological glucose concentrations and acts in synergy with signals that integrate messages originating from hypothalamic neurons and endocrine cells in gut and pancreas. Evidence exists that the extrapancreatic cells producing and secreting these (neuro)endocrine signals also exhibit a glucose sensor and an ability to integrate nutrient and (neuro)hormonal messages. Similarities in these cellular and molecular pathways provide a basis for a network of coordinated functions between distant cell groups, which is necessary for an appropriate control of nutrient homeostasis. The glucose sensor seems to be a fundamental component of these control mechanisms. Its molecular characterization is most advanced in pancreatic ␤-cells, with important roles for glucokinase and mitochondrial oxidative fluxes in the regulation of ATPsensitive K + channels. Other glucose-sensitive cells in the endocrine pancreas, hypothalamus, and gut were found to share some of these molecular characteristics. We propose that similar metabolic signaling pathways influence the function of pancreatic ␣-cells, hypothalamic neurons, and gastrointestinal endocrine and neural cells.

There is considerable controversy regarding epigenetic inheritance in mammalian gametes. Using in vitro fertilization to ensure exclusive inheritance via the gametes, we show that a parental high-fat diet renders offspring more susceptible to developing obesity and diabetes in a sex- and parent of origin-specific mode. The epigenetic inheritance of acquired metabolic disorders may contribute to the current obesity and diabetes pandemic.

Glucose homeostasis is controlled by a glucose sensor in pancreatic fl-cells. Studies on rodent fl-cells have suggested a role for GLUT2 and glucokinase in this control function and in mechanisms leading to diabetes. Little direct evidence exists so far to implicate these two proteins in glucose recognition by human (3-cells. The present in vitro study investigates the role of glucose transport and phosphorylation in fl-cell preparations from nondiabetic human pancreata. Human fl-cells differ from rodent f8-cells in glucose transporter gene expression (predominantly GLUT1 instead of GLUT2), explaining their low K. (3 mmol/liter) and low V m^x (3 mmol/min per liter) for 3-0-methyl glucose transport. The 100-fold lower GLUT2 abundance in human versus rat fl-cells is associated with a 10-fold slower uptake of alloxan, explaining their resistance to this rodent diabetogenic agent. Human and rat f-cells exhibit comparable glucokinase expression with similar flux-generating influence on total glucose utilization. These data underline the importance of glucokinase but not of GLUT2 in the glucose sensor of human fl-cells. (J. Clin. Invest 96:2489-2495

Previous studies on rat beta cells in vitro have suggested that insulin release is synergistically regulated by signalling molecules derived from glucose metabolism on the one hand and adenylate cyclase stimulation by glucagon or related peptides on the other [1±3]. In rodent beta cells, regulation of the cAMPdependent signalling pathway has been shown [3±7] to depend on expression of specific receptors for glucagon-like peptide-1-(7±36) amide (GLP-1), glucosedependent insulinotropic polypeptide (GIP) and glucagon. The gastrointestinal hormones GLP-1 and GIP effectively increase glucose-induced insulin release in vitro [8±10]; their pivotal role as incretin hormones has been recently illustrated in two mouse models with homozygous null mutations in the respective genes [11,12]. It is not clear whether similar mechanisms operate in human beta cells. More than three decades ago insulin release in humans was shown to be dually stimulated by glucose and glucagon [13,14], the glucagon effect appearing independent of enhanced glucose mobilisation from the liver ]-glucagon-amide (n = 8; p < 0.05), indicating participation of endogenously released glucagon in the process of glucose-induced insulin release. The glucagon-receptor antagonist also suppressed the potentiation of glucose-induced insulin release by addition of 10 nmol/l glucagon. Conclusion/interpretation. These data suggest that human beta cells express functional glucagon receptors which can, similar to incretin hormone receptors, generate synergistic signals for glucose-induced insulin secretion.

Rat pancreatic a-and P-cells are critically dependent on hormonal signals generating cyclic AMP (cAMP) as a synergistic messenger for nutrient-induced hormone release. Several peptides of the glucagon-secretin family have been proposed as physiological ligands for cAMP production in P-cells, but their relative importance for islet function is still unknown. The present study shows expression at the RNA level in p-cells of receptors for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1(7-36) amide (GLP-I), while RNA from islet a-cells hybridized only with GIP receptor cDNA. Western blots confirmed that GLP-I receptors were expressed in P-cells and not in a-cells. Receptor activity, measured as cellular cAMP production after exposing islet P-cells for 15 min to a range of peptide concentrations, was already detected using 10 pmol/1 GLP-I and 50 pmol/1 GIP but required 1 nmol/1 glucagon. EC 50 values of GLP-I-and GIP-induced cAMP formation were comparable (0.2 nmol/1) and 45-fold lower than the EC g0 of glucagon (9 nmol/1). Maximal stimulation of cAMP production was comparable for the three peptides. In purified a-cells, 1 nmol/1 GLP-I failed to increase cAMP levels, while 10 pmol/1 to 10 nmol/1 GIP exerted similar stimulatory effects as in P-cells. In conclusion , these data show that stimulation of glucagon,