BUETTNER, ROLAND, JÜ RGEN SCHÖ LMERICH, AND L. CORNELIUS BOLLHEIMER. High-fat diets: modeling the metabolic disorders of human obesity in rodents. Obesity. 2007;15:798 -808. Research Methods and Procedures: High-fat (HF) diet feeding can induce obesity and metabolic disorders in rodents that resemble the human metabolic syndrome. However, this dietary intervention is not standardized, and the HF-induced phenotype varies distinctly among different studies. The question which HF diet type is best to model the metabolic deterioration seen in human obesity remains unclear. Therefore, in this review, metabolic data obtained with different HF diet approaches are compiled. Both whole-body and organ-specific diet effects are analyzed. Results: On the basis of these results, we conclude that animal fats and -6/ -9-containing plant oils can be used to generate an obese and insulin-resistant phenotype in rodents, whereas fish oil-fed animals do not develop these disorders. Discussion: Looking at the present data, it does not seem possible to define an ideal HF diet, and an exact definition of diet composition and a thorough metabolic characterization of the HF diet effects in a researcher's specific laboratory setting remains essential for metabolic studies with this model.

High-fat (HF)-diet rodent models have contributed significantly to the analysis of the pathophysiology of the insulin resistance syndrome, but their phenotype varies distinctly between different studies. Here, we have systematically compared the metabolic and molecular effects of different HF with varying fatty acid compositions. Male Wistar rats were fed HF diets (42% energy; fat sources: HF-L -lard; HF-O -olive oil; HF-C -coconut fat; HF-F -fish oil). Weight, food intake, whole-body insulin tolerance and plasma parameters of glucose and lipid metabolism were measured during a 12-week diet course. Liver histologies and hepatic gene expression profiles, using Affymetrix GeneChips, were obtained. HF-L and HF-O fed rats showed the most pronounced obesity and insulin resistance; insulin sensitivity in HF-C and HF-F was close to normal. Plasma -3 polyunsaturated fatty acid ( -3-PUFA) and saturated fatty acid (C 12 -C 14 , SFA) levels were elevated in HF-F and HF-C animals respectively. The liver histologies showed hepatic steatosis in HF-L, HF-O and HF-C without major inflammation. Hepatic SREBP1c-dependent genes were upregulated in these diets, whereas PPAR -dependent genes were predominantly upregulated in HF-F fed rats. We detected classical HF effects only in diets based on lard and olive oil (mainly long-chain, saturated (LC-SFA) and monounsaturated fatty acids (MUFA)). PUFA-or MC-SFA-rich diets did not induce insulin resistance. Diets based on LC-SFA and MUFA induced hepatic steatosis with SREBP1c activation. This points to an intact transcriptional hepatic insulin effect despite resistance to insulin's metabolic actions.

The pancreatic beta cell normally maintains a stable balance among insulin secretion, insulin production, and insulin degradation to keep optimal intracellular stores of the hormone. Elevated levels of FFA markedly enhance insulin secretion; however, the effects of FFA on insulin production and intracellular stores remain unclear. In this study, twofold elevation in total circulating FFA effected by infusion of lard oil and heparin into rats for 6 h under normoglycemic conditions resulted in a marked elevation of circulating insulin levels evident after 4 h, and a 30% decrease in pancreatic insulin content after a 6-h infusion in vivo. Adding 125 muM oleate to isolated rat pancreatic islets cultured with 5.6 mM glucose caused a 50% fall in their insulin content over 24 h, coupled with a marked enhancement of basal insulin secretion. Both effects of fatty acid were blocked by somatostatin. In contrast to the stimulatory effects of oleate on insulin secretion, glucose-induced proinsulin biosynthesis was inhibited by oleate up to 24 h, but was unaffected thereafter. This result was in spite of a two- to threefold oleate-induced increase in preproinsulin mRNA levels, underscoring the importance of translational regulation of proinsulin biosynthesis in maintaining beta cell insulin stores. Collectively, these results suggest that chronically elevated FFA contribute to beta cell dysfunction in the pathogenesis of NIDDM by significantly increasing the basal rate of insulin secretion. This increase in turn results in a decrease in the beta cell's intracellular stores that cannot be offset by commensurate FFA induction of proinsulin biosynthesis.

An age-dependent decline in skeletal muscle mass, strength, and endurance during the aging process is a physiological development, but several factors may exacerbate this process, leading to the threatening state of sarcopenia, frailty, and eventually higher mortality rates. Obesity appears to be such a promoting factor and has been linked in several studies to sarcopenia. The reason for this causal association remains poorly understood. Notwithstanding the fact that a higher body mass might simply lead to diminished physical activity and therefore contribute to a decline in skeletal muscle, several molecular mechanisms have been hypothesized. There could be an obesity derived intracellular lipotoxicity (i.e., elevated intramuscular levels of lipids and their derivatives), which induces apoptosis by means of an elevated oxidative stress. Paracrine mechanisms and inflammatory cytokines, such as CRP and IL-6 could be confounders of the actual underlying pathological mechanism. Due to a cross-talk of the hypothalamo-pituitary axis with nutritional status, obese subjects are more in a catabolic state of metabolism, with a higher susceptibility to muscle wasting under energy restriction. Obesity induces insulin resistance in the skeletal muscle, which consequently leads to perturbed metabolism, and misrouted signaling in the muscle cells. In obesity, muscle progenitor cells could differentiate to an adipocyte-like phenotype as a result of paracrine signals from (adipo)cytokines leading to a reduced muscular renewal capacity. The present review outlines current knowledge concerning possible pathways, which might be involved in the molecular pathogenesis of sarcopenic obesity.

Objective: Unexplained hepatic iron overload with increased serum ferritin (SF) values has been associated with the insulin resistance syndrome (IRS), defined by the presence of one or more of the following criteria: increased body mass index (BMI), diabetes, hyperlipidemia or hypertension. However, as yet the association between IRS and SF in a representative population has not been investigated. Methods: The study subjects participated in a nationwide epidemiological survey on metabolic disorders in the adult German population. The 1200 probands included in this study are representative of the German population. To eliminate major causes of secondary iron overload, 114 (9.5%) subjects with excessive alcohol consumption and 16 (1.5%) subjects with serological evidence for hepatitis B or C were excluded. For all remaining 1070 probands, complete clinical data of SF, HbA1c, known diabetes, BMI, cholesterol, high-density lipoprotein-cholesterol and blood pressure were available. Results: SF values were significantly increased in men and women with high BMI (. 25 kg/m 2 ), increased cholesterol (. 200 mg/dl), and increased systolic (. 160 mmHg) blood pressure, in women with diabetes, and in men with increased diastolic (. 95 mmHg) blood pressure. Furthermore, there was a significant correlation between the number of IRS criteria and SF. Conclusions: This study shows a significant correlation between SF and the presence of IRS criteria in a large representative population. Interestingly, the severity of the IRS seems to be associated with increased SF levels suggesting a causal connection. Further studies are required to investigate the pathophysiological mechanism and consequences of increased SF levels in patients with IRS.European Journal of Endocrinology 154 333-340