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ABSTRACT Oxymatrine, a quinolizidine alkaloid, has been widely used for the treatment of hepatitis. In this study, we investigated the hypoglycemic and hypolipidemic effects and new pharmacological activities of oxymatrine, [...]

Low-carbohydrate, high-fat ketogenic diets (KD) have been suggested to be more effective in promoting weight loss than conventional caloric restriction, whereas their effect on hepatic glucose and lipid metabolism and the mechanisms by which they may promote weight loss remain controversial. The aim of this study was to explore the role of KD on liver and muscle insulin sensitivity, hepatic lipid metabolism, energy expenditure, and food intake. Using hyperinsulinemic-euglycemic clamps, we studied insulin action in mice fed a KD or regular chow (RC). Body composition was assessed by [sup.1]H magnetic resonance spectroscopy. Despite being 15% lighter (P < 0.001) than RC-fed mice because of a 17% increase in energy expenditure (P < 0.001), KD-fed mice manifested severe hepatic insulin resistance, as reflected by decreased suppression (0% vs. 100% in RC-fed mice, P < 0.01) of endogenous glucose production during the clamp. Hepatic insulin resistance could be attributed to a 350% increase in hepatic diacylglycerol content (P < 0.001), resulting in increased activation of PKC[epsilon] (P < 0.05) and decreased insulin receptor substrate-2 tyrosine phosphorylation (P < 0.01). Food intake was 56% (P < 0.001) lower in KD-fed mice, despite similar caloric intake, and could partly be attributed to a more than threefold increase (P < 0.05) in plasma N-acylphosphatidylethanolamine concentrations. In conclusion, despite preventing weight gain in mice, KD induces hepatic insulin resistance secondary to increased hepatic diacylglycerol content. Given the key role of nonalcoholic fatty liver disease in the development of type 2 diabetes and the widespread use of KD for the treatment of obesity, these results may have potentially important clinical implications. nonalcoholic fatty liver disease; weight loss; diacylglycerol; ceramide; protein kinase C[epsilon]; FGF21 doi: 10.1152/ajpendo.00361.2010.

High-fat diets are known to decrease muscle protein synthesis, the adaptation to overload, and insulin sensitivity. Conditions that disrupt endoplasmic reticulum (ER) homeostasis lead to the activation of the unfolded protein response (UPR) that is associated with decreases in protein synthesis, chronic inflammation, and insulin resistance. The purpose of the present study was to establish whether ER stress is induced by a high-fat diet in skeletal muscle and whether ER stress can decrease mTORC1 activity and protein synthesis in muscle cells. Two independent protocols of high-fat feeding activated the UPR in mice. In the first study, mice consuming a high-fat diet containing 70% fat and < 1% carbohydrates for 6 wk showed higher markers of the UPR (BiP, IRE1[alpha], and MBTPS2) in the soleus and in the tibialis anterior muscles and ATF4 in the tibialis anterior (P < 0.05). In the second study, a 20-wk high-fat diet containing 46% fat and 36% carbohydrates also increased BiP, IRE1[alpha], and phospho-PERK protein and the expression of ATF4, CHOP, and both the spliced and unspliced forms of XBP1 in the plantar flexors (P < 0.05). In [C.sub.2][C.sub.12] muscle cells, tunicamycin, thapsigargin, and palmitic acid all increased UPR markers and decreased phosphorylation of S6K1 (P < 0.05). Collectively, these data show that a high-fat diet activates the UPR in mouse skeletal muscle in vivo. In addition, in vitro studies indicate that palmitic acid, and other well-known ER stress inducers, triggered the UPR in myogenic cells and led to a decrease in protein synthesis and mTORC1 activity. endoplasmic reticulum stress; binding protein; X box binding protein-1; ribosomal protein S6 kinase; protein synthesis doi: 10.1152/ajpendo.00038.2010.

We investigated the effects of eicosapentaenoic acid (EPA) on prevention (P) and reversal (R) of high saturated-fat (HF) diet-induced obesity and glucose-insulin homeostasis. Male C57BL/6J mice were fed low-fat (LF; 10% energy from fat), HF (45% energy from fat), or a HF-EPA-P (45% energy from fat; 36 g/kg EPA) diet for 11 wk. A 4th group was initially fed HF for 6 wk followed by the HF-EPA-R diet for 5 wk. As expected, mice fed the HF diet developed obesity and glucose intolerance. In contrast, mice fed the HF-EPA-P diet maintained normal glucose tolerance despite weight gain compared with the LF group. Whereas the HF group developed hyperglycemia and hyperinsulinemia, both HF-EPA groups (P and R) exhibited normal glycemia and insulinemia. Further, plasma adiponectin concentration was lower in the HF group but was comparable in the LF and HF-EPA groups, suggesting a role of EPA in preventing and improving insulin resistance induced by HF feeding. Further analysis of adipose tissue adipokine levels and proteomic studies in cultured adipocytes indicated that dietary EPA supplementation of HF diets was associated with reduced adipose inflammation and lipogenesis and elevated markers of fatty acid oxidation. In C57BL/6J mice, EPA minimized saturated fat-induced insulin resistance and this is in part mediated by its effects on fatty acid oxidation and inflammation. J. Nutr. 140: 1915-1922, 2010. doi: 10.3945/jn.110.125732.

Adult rats chronically fed a high-fat (HF) diet maintain reduced sensitivity to cholecystokinin (CCK). We hypothesized that, similar to adult rats, pups fed a HF diet would also exhibit reduced sensitivity to CCK. To test this, male pups fed low-fat (LF) and HF isoenergetic (16.2 k J/g) diets were administered CCK intraperitoneally (0.125-1 g/kg) 1 wk following dietary adaptation. After receiving 0.5 g/kg CCK, pups fed the HF diet suppressed food intake less (8.9 [+ or -] 5.0%) than pups fed the LF diet (28.9 [+ or -] 4.7%; P < 0.05) relative to intakes after saline administration. We then assessed the development and extinction of changes in CCK sensitivity by switching the diets between the groups. The HF-fed group, when switched to the LF diet, regained sensitivity by wk 4 and suppressed food intake following administration of 0.25 g/kg CCK (33.1 [+ or -] 5.7%; P < 0.05). The LF-fed group, when switched to the HF diet, lost sensitivity by wk 2 and did not suppress food intake after administrations of CCK compared with saline. Finally, we examined if HF-fed rats have an increased sensitivity to corn oil during brief access tests using a multibottle gustometer. At oil concentrations of 25, 75, and 100%, rats fed the HF diet sampled more oil than LF-fed rats (P < 0.05). These findings demonstrate that male rat pups fed a HF diet exhibit reduced sensitivity to CCK, the development of this reduced sensitivity is quicker than its extinction, and rats consuming a HF diet have increased oral sensitivity to oils. J. Nutr. 140: 1698-1703, 2010. doi: 10.3945/jn.110.124149.

Increased sympathetic nerve activity is associated with obesity-related hypertension, but the underlying central neural mechanisms are not clear. We examined the role of the hypothalamic paraventricular nucleus (PVN) in the regulation of sympathetic nerve activity in rats fed a normal chow diet (controls) and rats fed a high-tat diet (36% fat) over 12 wk. The effects on blood pressure, heart rate, and lumbar sympathetic nerve activity (LSNA) induced by microinjection of the GABAA receptor agonist muscimol or the antagonist bicuculline were monitored in anesthetized rats. Body weight of rats fed the high-fat diet was not significantly different from controls, but a significant 80% increase in epididymal fat mass, significantly elevated fasting blood glucose, and significantly impaired glucose tolerance were observed in rats fed the high-fat diet. Resting blood pressure and heart rate were not significantly different between rats fed the high-fat diet and controls. Muscimol microinjected into the PVN elicited a greater reduction of blood pressure and LSNA in rats fed the high-fat diet than controls: -14 [+ or -] 6 vs. -7 [+ or -] 2 mmHg and -35 [+ or -] 6 vs. -10 [+ or -] 9% (P < 0.05). Microinjection of bicuculline into the PVN increased blood pressure and LSNA, but the responses were similar in rats fed the high-fat diet and controls. In conclusion, the role of the paraventricular nucleus in cardiovascular regulation can be altered by a diet high in fat, even when hypertension and obesity are absent. high-fat diet; paraventricular nucleus of hypothalamus; lumbar sympathetic nerve activity doi:10.1152/ajpregu.00558.2009

Am J Physiol Gastrointest Liver Physiol 298:G107~3116, 2010. First published October 29, 2009; doi: 10.1152/ajpgi.00391.2009.--Recruited adipose tissue macrophages contribute to chronic and low-grade inflammation causing insulin resistance in obesity. Similarly, we hypothesized here that Kupffer cells, the hepatic resident macrophages, play a pathogenic role in hepatic insulin resistance induced by a high-fat diet. Mice were fed a normal diet or high-fat diet for 3 days. Kupffer cell activation was evaluated by immunohistochemistry and quantitative RT-PCR. Insulin sensitivity was assessed in vivo by hyperinsulinemic-euglycemic clamp and insulin-activated signaling was investigated by Western blot. Liposome-encapsulated clodronate was injected intravenously to deplete macrophages prior to a short-term exposure to high-fat diet. Here, we characterized a short-term high-fat diet model in mice and demonstrated early hepatic insulin resistance and steatosis concurrent with Kupffer cell activation. We demonstrated that selective Kupffer cell depletion obtained by intravenous clodronate, without affecting adipose tissue macrophages, was sufficient to enhance insulin-dependent insulin signaling and significantly improve hepatic insulin sensitivity in vivo in this short-term high-fat diet model. Our study clearly shows that hepatic macrophage response participates to the onset of high-fat diet-induced hepatic insulin resistance and may therefore represent an attractive target for prevention and treatment of diet- and obesity-induced insulin resistance. macrophage; liver; steatosis; liposomes; high-fat diet

Jorgensen W, Gam C, Andersen JL, Schjerling P, Scheibye-Knudsen M, Mortensen OH, Grunnet N, Nielsen MO, Quistorff B. Changed mitochondrial function by pre- and/or postpartum diet alterations in sheep. Am J Physiol Endocrinol Metab 297: E1349-E1357, 2009. First published October 13, 2009; doi: 10.1152/ajpendo.00505.2009.--In a sheep model, we investigated diet effects on skeletal muscle mitochondria to look for fetal programming. During pregnancy, ewes were fed normally (N) or were 50% food restricted (L) during the last trimester, and lambs born to these ewes received a normal (N) or a high-fat diet (H) for the first 6 mo of life. We examined mitochondrial function in permeabilized muscle fibers from the lambs at 6 mo of age (adolescence) and after 24 mo of age (adulthood). The postpartum H diet for the lambs induced an ~30% increase (P < 0.05) of mitochondrial [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] and an ~50% increase (P < 0.05) of the respiratory coupling ratio (RCR) combined with lower levels of UCP3 and PGC-1[alpha] mRNA levels (P < 0.05). These effects proved to be reversible by a normal diet from 6 to 24 mo of age. However, at 24 too, a long-term effect of the maternal gestational diet restriction (fetal programming) became evident as a lower [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] (~40%, P < 0.05), a lower state 4 respiration (~40%, P < 0.05), and lower RCR (~15%, P < 0.05). Both PGC-l[alpha] and UCP3 mRNA levels were increased (P < 0.05). Two analyzed muscles were affected differently, and muscle rich in type I fibers was more susceptible to fetal programming. We conclude that fetal programming, seen as a reduced [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] in adulthood, results from gestational undernutrition. Postnatal high-fat diet results in a pronounced RCR and [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII], increase in adolescence. However, these effects are reversible by diet correction and are not maintained in adulthood. metabolic syndrome; high-fat diet; nutrient restriction; maternal diet; respiratory coupling ratio doi: 10.1152/ajpendo.00505.2009

Contributing to the obesity epidemic, there is increasing evidence that overconsumption of high-fat foods may be analogous to drug addiction in that the palatability of these foods is associated with activation of specific reward pathways in the brain. With this perspective, we report that mice lacking the G protein [[gamma].sub.3]-subunit ([Gng3.sup.-/-] mice) show resistance to high-fat diet-induced weight gain over the course of a 12-wk study. Compared with [Gng3.sup.+/+] controls, female [Gng3.sup.-/-] mice exhibit a 40% reduction in weight gain and a 53% decrease in fat pad mass, whereas male [Gng3.sup.-/-] mice display an 18% reduction in weight gain and no significant decrease in fat pad mass. The basis for the lowered weight gain is related to reduced food consumption for female and male [Gng3.sup.-/-] mice of 13% and 14%, respectively. Female [Gng3.sup.-/-] mice also show a lesser preference for high-fat chow than their female [Gng3.sup.+/+] littermates, suggesting an attenuated effect on a reward pathway associated with overconsumption of fat. One possible candidate is the [mu]-opioid receptor (Oprml) signaling cascade. Supporting a defect in this signaling pathway, [Gng3.sup.-/-] mice show marked reductions in both acute and chronic morphine responsiveness, as well as increases in endogenous opioid mRNA levels in reward-related regions of the brain. Taken together, these data suggest that the decreased weight gain of [Gng3.sup.-/-] mice may be related to a reduced rewarding effect of the high-fat diet resulting from a defect in Oprml signaling and loss of the G protein [[gamma].sub.3]-subunit. lean: reward; G protein-coupled receptor doi: 10.1152/ajpregu.00308.2009.

To test whether chronic enhanced blood flow alters insulin-stimulated glucose uptake, we measured skeletal muscle glucose uptake in chow-fed and high-fat-fed mice injected with adenovirus containing modified angiopoietin-1, COMP-Ang1, via euglycemic-hyperinsulinemic clamp. Blood flow rates and platelet endothelial cell adhesion molecule-1 positive endothelial cells in the hindlimb skeletal muscle were elevated in COMP-Ang1 compared with control LacZ. Whole body glucose uptake and whole body glycogen/lipid synthesis were elevated in COMP-Ang1 compared with LacZ in chow diet. High-fat diet significantly reduced whole body glucose uptake and whole body glycolysis in LacZ mice, whereas high-fat-fed COMP-Ang1 showed a level of whole body glucose uptake that was comparable with chow-fed LacZ and showed increased glucose uptake compared with high-fat-fed LacZ. Glucose uptake and glycolysis in gastrocnemius muscle of chow-fed COMP-Ang1 were increased compared with chow-fed LacZ. High-fat diet-induced whole body insulin resistance in the LacZ was mostly due to ~40% decrease in insulin-stimulated glucose uptake in skeletal muscle. In contrast, COMP-Ang 1 prevented diet-induced skeletal muscle insulin resistance compared with high-fat-fed LacZ. Akt phosphorylation in skeletal muscle was increased in COMP-Ang1 compared with LacZ in both chow-fed and high-fat-fed groups. These results suggest that increased blood flow by COMP-Angl increases insulin-stimulated glucose uptake and prevents high-fat diet-induced insulin resistance in skeletal muscle. glucose uptake; high-fat diet; hyperinsulinemic-euglycemic clamp

The epidemics of obesity and metabolic disorders have well-recognized health and economic burdens. Pharmacologic treatments for these diseases remain unsatisfactory with respect to both efficacy and side-effect profiles. Here, we have identified a potential central role for T-type calcium channels in regulating body weight maintenance and sleep. Previously, it was shown that mice lacking [Ca.sub.V]3.1 T-type calcium channels have altered sleep/wake activity. We found that these mice were also resistant to high-fat diet--induced weight gain, without changes in food intake or sensitivity to high-fat diet--induced disruptions of diurnal rhythm. Administration of a potent and selective antagonist of T-type calcium channels, TTA-A2, to normal-weight animals prior to the inactive phase acutely increased sleep, decreased body core temperature, and prevented high-fat diet--induced weight gain. Administration of TTA-A2 to obese rodents reduced body weight and fat mass while concurrently increasing lean muscle mass. These effects likely result from better alignment of diurnal feeding patterns with daily changes in circadian physiology and potentially an increased metabolic rate during the active phase. Together, these studies reveal what we believe to be a previously unknown role for T-type calcium channels in the regulation of sleep and weight maintenance and suggest the potential for a novel therapeutic approach to treating obesity., Introduction While the individual consequences of metabolic syndrome and sleep disorders are widely recognized, the interplay between sleep and metabolism is only recently gaining widespread attention (1), (2), (3), (4), [...]

Maternal obesity is thought to increase the offspring&apos;s risk of juvenile obesity and metabolic diseases; however, the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Here, we investigated in nonhuman primates the effect of chronic high-fat diet (HFD) on the development of fetal metabolic systems. We found that fetal offspring from both lean and obese mothers chronically consuming a HFD had a 3-fold increase in liver triglycerides (TGs). In addition, fetal offspring from HFD-fed mothers (O-HFD) showed increased evidence of hepatic oxidative stress early in the third trimester, consistent with the development of nonalcoholic fatty liver disease (NAFLD). O-HFD animals also exhibited elevated hepatic expression of gluconeogenic enzymes and transcription factors. Furthermore, fetal glycerol levels were 2-fold higher in O-HFD animals than in control fetal offspring and correlated with maternal levels. The increased fetal hepatic TG levels persisted at P180, concurrent with a 2-fold increase in percent body fat. Importantly, reversing the maternal HFD to a low-fat diet during a subsequent pregnancy improved fetal hepatic TG levels and partially normalized gluconeogenic enzyme expression, without changing maternal body weight. These results suggest that a developing fetus is highly vulnerable to excess lipids, independent of maternal diabetes and/or obesity, and that exposure to this may increase the risk of pediatric NAFLD., Introduction The prevalence of childhood obesity has increased dramatically in the United States over the past several decades. According to the most recent National Health and Nutrition Examination Survey (NHANES) [...]

Maternal obesity is becoming more prevalent. We used borderline hypertensive rats (BHR) to investigate whether a high-fat diet at different stages of development has adverse programming consequences on metabolic parameters and blood pressure. Wistar dams were fed a high- or low-fat diet for 6 wk before mating with spontaneously hypertensive males and during the ensuing pregnancy. At birth, litters were fostered to a dam from the same diet group as during gestation or to the alternate diet condition. Female offspring were weaned on either control or 'junk food' diets until about 6 mo of age. Rats fed the high-fat junk food diet were hyperphagic relative to their chow-fed controls. The junk food-fed rats were significantly heavier and had greater fat pad mass than those rats maintained on chow alone. Importantly, those rats suckled by high-fat dams had heavier fat pads than those suckled by control diet dams. Fasting serum leptin and insulin levels differed as a function of the gestational, lactational, and postweaning diet histories. Rats gestated in, or suckled by high-fat dams, or maintained on the junk food diet were hyperleptinemic compared with their respective controls. Indirect blood pressure did not differ as a function of postweaning diet, but rats gestated in the high-fat dams had lower mean arterial blood pressures than those gestated in the control diet dams. The postweaning dietary history affected food-motivated behavior; junk food-fed rats earned less food pellets on fixed (FR) and progressive (PR) ratio cost schedules than chow-fed controls. In conclusion, the effects of maternal high-fat diet during gestation or lactation were mostly small and transient. The postweaning effects of junk food diet were evident on the majority of the parameters measured, including body weight, fat pad mass, serum leptin and insulin levels, and operant performance. developmental programming; blood pressure; metabolic syndrome; motivation

The objective of this study was to determine the optimal conditions under which to assess glucose tolerance in chow- and high-fat-fed C57BL/6J mice. Mice were fed either chow or high-fat diet for 8 wk. Variables tested were fasting duration (0-, 3-, 6-, and 24-h and overnight fasting), route of administration (intraperitoneal vs. oral) load of glucose given (2, 1, or 0.5 g/kg and fixed 50-mg dose), and state of consciousness. Basal glucose concentrations were increased in high-fat- compared with chow-fed mice following 6 h of fasting (9.1 [+ or -] 0.3 vs. 7.9 [+ or -] 0.4 mmol/l P = 0.01). Glucose tolerance was most different and therefore significant (P = 0.001) in high-fat-fed mice after 6 h of fasting (1,973 [+ or -] 96 vs. 1,248 [+ or -] 83 mmol x [l.sup.-1] x 120 [min.sup.-1]). The difference in glucose tolerance was greater following an OGTT (142%), in contrast to an IPGTT, with a 127% difference between high fat and chow. We also found that administering 2 g/kg of glucose resulted in a greater level of significance (P = 0.0008) in glucose intolerance in high-fat-compared with chow-fed mice. A fixed dose of 50 mg glucose regardless of body weight was enough to show glucose intolerance in high-fat- vs. chow-fed mice. Finally, high-fat-fed mice showed glucose intolerance compared with their chow-fed counterparts whether they were tested under conscious or anesthetized conditions. We conclude that 2 g/kg glucose administered orally following 6 h of fasting is best to assess glucose tolerance in mice under these conditions. intraperitoneal glucose tolerance test; oral glucose tolerance test; fasting; high-fat feeding; C57BL/6J

Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin (1), but other substrates of the insulin receptor kinase, such as Gabl, c-Cbl, SH2-B and APS, are also of physiological relevance (2-5). Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling (6-8), its role in energy homeostasis has remained unclear. Here we show that Dok1 regulates adiposity. Expression of Dok1 in white adipose tissue was markedly increased in mice fed a high-fat diet, whereas adipocytes lacking this adapter were smaller and showed a reduced hypertrophic response to this dietary manipulation. Dok1-deficient mice were leaner and showed improved glucose tolerance and insulin sensitivity compared with wild-type mice. Embryonic fibroblasts from Dok1-deficient mice were impaired in adipogenic differentiation, and this defect was accompanied by an increased activity of the protein kinase ERK and a consequent increase in the phosphorylation of peroxisome proliferator-activated receptor (PPAR)-[gamma] on Ser112. Mutation of this negative regulatory site for the transactivation activity of PPAR-[gamma] blocked development of the lean phenotype caused by Dok1 ablation. These results indicate that Dok1 promotes adipocyte hypertrophy by counteracting the inhibitory effect of ERK on PPAR-[gamma] and may thus confer predisposition to diet-induced obesity., We and others have shown that tyrosine-phosphorylated Dok1 binds and recruits p120 Ras GTPase-activating protein (rasGAP) as well as the adapter protein Nck, thereby regulating mitogenic signaling mediated by Ras [...]

The gut hormone gastric inhibitory polypeptide (GIP) plays a key role in glucose homeostasis and lipid metabolism. This study investigated the effects of administration of a stable and specific GIP receptor antagonist, ([Pro.sup.3])GIP, in mice previously fed a high-fat diet for 160 days to induce obesity and related diabetes. Daily intraperitoneal injection of ([Pro.sup.3])GIP over 50 days significantly decreased body weight compared with saline-treated controls, with a modest increase in locomotor activity but no change of high-fat diet intake. Plasma glucose, glycated hemoglobin, and pancreatic insulin were restored to levels of chow-fed mice, and circulating triglyceride and cholesterol were significantly decreased. ([Pro.sup.3])GIP treatment also significantly decreased circulating glucagon and corticosterone, but concentrations of GLP-1, GIP, resistin, and adiponectin were unchanged. Adipose tissue mass, adipocyte hypertrophy, and deposition of triglyceride in liver and muscle were significantly decreased. These changes were accompanied by significant improvement of insulin sensitivity, meal tolerance, and normalization of glucose tolerance in ([Pro.sup.3])GIP-treated high-fat-fed mice. ([Pro.sup.3])GIP concentrations peaked rapidly and remained elevated 24 h after injection. These data indicate that GIP receptor antagonism using (Pro3)GIP provides an effective means of countering obesity and related diabetes induced by consumption of a high-fat, energy-rich diet. gastric inhibitory polypeptide; antagonist; high-fat feeding

Obesity and cigarette smoking are both important risk factors for insulin resistance, cardiovascular disease, and cancer. Smoking reduces appetite, which makes many people reluctant to quit. Few studies have documented the metabolic impact of combined smoke exposure (se) and high-fat-diet (HFD). Neuropeptide Y (NPY) is a powerful hypothalamic feeding stimulator that promotes obesity. We investigated how chronic se affects caloric intake, adiposity, plasma hormones, inflammatory mediators, and hypothalamic NPY peptide in animals fed a palatable HFD. Balb/c mice (5 wk old, male) were exposed to smoke (2 cigarettes, twice/day, 6 days/wk, for 7 wk) with or without HFD. Sham-exposed mice were handled similarly without se. Plasma leptin, hypothalamic NPY, and adipose triglyceride lipase (ATGL) mRNA were measured. HFD induced a 2.3-fold increase in caloric intake, increased adiposity, and glucose in both sham and se cohorts. Smoke exposure decreased caloric intake by 23%, with reduced body weight in both dietary groups. Fat mass and glucose were reduced only by se in the cho-fed animals. ATGL mRNA was reduced by HFD in se animals. Total hypothalamic NPY was reduced by HFD, but only in sham-exposed animals; se increased arcuate NPY. We conclude that although se ameliorated hyperphagia and reversed the weight gain associated with HFD, it failed to reverse fat accumulation and hyperglycemia. The reduced ATGL mRNA expression induced by combined HFD and se may contribute to fat retention. Our data support a powerful health message that smoking in the presence of an unhealthy Western diet increases metabolic disorders and fat accumulation. adipose triglyceride lipase; appetite; leptin; neuropeptide Y; tumor necrosis factor-[alpha]

Epidemiological and animal studies suggest that the alteration of hormonal and metabolic environment during fetal and neonatal development can contribute to development of metabolic syndrome in adulthood. In this paper, we investigated the impact of maternal high-fat (HF) diet on hypothalamic leptin sensitivity and body weight gain of offspring. Adult Wistar female rats received a HF or a control normal-fat (C) diet for 6 wk before gestation until the end of the suckling period. After weaning, pups received either C or HF diet during 6 wk. Body weight gain and metabolic and endocrine parameters were measured in the eight groups of rats formed according to a postweaning diet, maternal diet, and gender. To evaluate hypothalamic leptin sensitivity in each group, STAT-3 phosphorylation was measured in response to leptin or saline intraperitoneal bolus. Pups exhibited similar body weights at birth, but at weaning, those born to HF dams weighed significantly less (-12%) than those born to C dams. When given the HF diet, males and females born to HF dams exhibited smaller body weight and feed efficiency than those born to C dams, suggesting increased energy expenditure programmed by the maternal HF diet. Thus, maternal HF feeding could be protective against adverse effects of the HF diet as observed in male offspring of control dams: overweight (+ 17%) with hyperleptinemia and hyper-insulinemia. Furthermore, offspring of HF dams fed either C or HF diet exhibited an alteration in hypothalamic leptin-dependent STAT-3 phosphorylation. We conclude that maternal high-fat diet programs a hypothalamic leptin resistance in offspring, which, however, fails to increase the body weight gain until adulthood. leptin resistance; hypothalamus; high-fat diet

We previously reported an exaggerated endocrine and weight loss response to stress in rats fed a high-fat (HF) diet for 5 days. Others report blunted stress-induced anxiety in rats made obese on a HF diet. Experiments described here tested whether sensitivity to stress-related peptides was changed in obese and nonobese HF-fed rats. Third ventricle infusion of corticotropin-releasing factor (CRF) in rats made obese on HF diet (40% kcal fat) produced an exaggerated hypophagia, which is thought to be mediated by CR[F.sub.2] receptors. Obese rats responded to a lower dose of CRF for a longer time than rats fed a low-fat (LF) diet (12% kcal fat). CRF-induced release of corticosterone, which is thought to be mediated by CR[F.sub.1] receptors, was not exaggerated in obese HF-fed rats. In contrast, rats fed HF diet for 5 days showed the same food intake and corticosterone response to CRF as LF-fed rats. CRF mRNA expression in the paraventricular nucleus of the hypothalamus was stimulated by mild stress (ip saline injection and placement in a novel cage) in LF-fed rats but not in rats fed HF diet for 5 days because of a nonsignificant increase in expression in nonstressed HF-fed rats. In addition, nonstressed levels of urocortin (UCN) I mRNA expression in the Edinger-Westphal nucleus were significantly inhibited in HF-fed rats. These data suggest that rats that have become obese on a HF diet show a change in responsiveness to stress peptides, whereas the increased stress response in nonobese HF-fed rats may he associated with changes in basal CRF and UCN I mRNA expression. rats; food intake; corticosterone; corticotropin-releasing factor mRNA; urocortin I mRNA

Ketogenic diets have been used as an approach to weight loss on the basis of the theoretical advantage of a low-carbohydrate, high-fat diet. To evaluate the physiological and metabolic effects of such diets on weight we studied mice consuming a very-low-carbohydrate, ketogenic diet (KD). This diet had profound effects on energy balance and gene expression. C57BL/6 mice animals were fed one of four diets: KD; a commonly used obesogenic high-fat, high-sucrose diet (HF); 66% caloric restriction (CR); and control chow (C). Mice on KD ate the same calories as mice on C and HF, but weight dropped and stabilized at 85% initial weight, similar to CR. This was consistent with increased energy expenditure seen in animals fed KD vs. those on C and CR. Microarray analysis of liver showed a unique pattern of gene expression in KD, with increased expression of genes in fatty acid oxidation pathways and reduction in lipid synthesis pathways. Animals made obese on HF and transitioned to KD lost all excess body weight, improved glucose tolerance, and increased energy expenditure. Analysis of key genes showed similar changes as those seen in lean animals placed directly on KD. Additionally, AMP kinase activity was increased, with a corresponding decrease in ACC activity. These data indicate that KD induces a unique metabolic state congruous with weight loss. liver; gene expression doi:10.1152/ajpendo.00717.2006.

With the worldwide epidemic of metabolic syndrome (MetS), the proportion of women that are overweight/obese and overfed during pregnancy has increased. The resulting abnormal uterine environment may have deleterious effects on fetal metabolic programming and lead to MetS in adulthood. A balanced/restricted diet and/or physical exercise often improve metabolic abnormalities in individuals with obesity and type 2 diabetes mellitus (T2D). We investigated whether reducing fat intake during the periconceptual/gestation/lactation period in mothers with high-fat diet (HFD)-induced obesity could be used to modify fetal/ neonatal MetS programming positively, thereby preventing MetS. First generation (F1) C57BL/6J female mice with HFD-induced obesity and T2D were crossed with F1 males on control diet (CD). These F1 females were switched to a CD during the periconceptual/ gestation/lactation period. At weaning, both male and female second generation (F2) mice were fed a HFD. Weight, caloric intake, lipid parameters, glucose, and insulin sensitivity were assessed. Sensitivity/resistance to the HFD differed significantly between generations and sexes. A similar proportion of the F1 and F2 males (80%) developed hyperphagia, obesity, and T2D. In contrast, a significantly higher proportion of the F2 females (43%) than of the previous F1 generation (17%) were resistant (P < 0.01). Despite having free access to the HFD, these female mice were no longer hyperphagic and remained lean, with normal insulin sensitivity and glycemia but mild hypercholesterolemia and glucose intolerance, thus displaying a 'satiety phenotype.' This suggests that an appropriate dietary fatty acid profile and intake during the periconceptual/gestation/lactation period helps the female offspring to cope with deleterious intrauterine conditions. epigenetics; nutrition; metabolic syndrome; fetal programming

We examined whether the additional demand for insulin secretion imposed by dietary saturated fat-induced insulin resistance during pregnancy is accommodated at late pregnancy, already characterized by insulin resistance. We also assessed whether effects of dietary saturated fat are influenced by PPAR[alpha] activation or substitution of 7% of dietary fatty acids (FAs) with long-chain [omega]-3 FA, manipulations that improve insulin action in the nonpregnant state. Glucose tolerance at day 19 of pregnancy in the rat was impaired by high-saturated-fat feeding throughout pregnancy. Despite modestly enhanced glucose-stimulated insulin secretion (GSIS) in vivo, islet perifusions revealed an increased glucose threshold and decreased glucose responsiveness of GSIS in the saturated-fat-fed pregnant group. Thus, insulin resistance evoked by dietary saturated fat is partially countered by augmented insulin secretion, but compensation is compromised by impaired islet function. Substitution of 7% of saturated FA with long-chain [omega]-3 FA suppressed GSIS in vivo but did not modify the effect of saturated-fat feeding to impair GSIS by perifused islets. PPAR[alpha] activation (24 h) rescued impaired islet function that was identified using perifused islets, but GSIS in vivo was suppressed such that glucose tolerance was not improved, suggesting modification of the feedback loop between insulin action and secretion. islet function; peroxisome proliferator-activated receptor-[alpha]; fatty acids; insulin resistance

Adiponectin and its receptors play an important role in energy homeostasis and insulin resistance, but their regulation remains to be fully elucidated. We hypothesized that high-fat diet would decrease adiponectin but increase adiponectin receptor (AdipoR1 and AdipoR2) expression in diet-induced obesity (DIO)-prone C57BL/6J and DIO-resistant A/J mice. We found that circulating adiponectin and adiponectin expression in white adipose tissue are higher at baseline in C57BL/6J mice compared with A/J mice. Circulating adiponectin increases at 10 wk but decreases at 18 wk in response to advancing age and high-fat feeding. However, adiponectin levels corrected for visceral fat mass and adiponectin mRNA expression in WAT are affected by high-fat feeding only, with both being decreased after 10 wk in C57BL/6J mice. Muscle AdipoR1 expression in both C57BL/6J and A/J mice and liver adipoR1 expression in C57BL/6J mice increase at 18 wk of age. High-fat feeding increases both AdipoR1 and AdipoR2 expression in liver in both strains of mice and increases muscle AdipoR1 expression in C57BL/6J mice after 18 wk. Thus advanced age and high-fat feeding, both of which are factors that predispose humans to obesity and insulin resistance, are associated with decreasing adiponectin and increasing AdipoR1 and/or AdipoR2 levels. diet-induced obesity; insulin resistance; adiponectin; adiponectin receptor 1; adiponectin receptor 2

Growth hormone (GH), acting through its receptor (GHR), is essential for somatic growth and development and maintaining metabolic homeostasis. GHR gene-deficient (GH[R.sup.-/-]) mice exhibit drastically diminished insulin-like growth factor-I (IGF-I) levels, proportional growth retardation, elevated insulin sensitivity, and reduced islet [beta]-cell mass. Unlike the liver, which is mostly unaffected by changes in IGF-I level, skeletal muscles express high levels of IGF-I receptor (IGF-IR). The net result of a concurrent deficiency in the actions of both GH and IGF-I, which exert opposite influences on insulin responsiveness, has not been evaluated. We studied insulin-stimulated early responses in the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), and p85 subunit of phosphatidylinositol 3-kinase. Upon in vivo insulin stimulation, skeletal muscles of GH[R.sup.-/-] mice exhibit transient delayed responses in IR and IRS-1 phosphorylation but normal levels of p85 association with IRS-1. This is in contrast to normal/elevated insulin responses in hepatocytes and indicates tissue-specific effects of GHR gene deficiency. In addition to stimulating normal islet cell growth, GH may participate in islet cell overgrowth, which compensates for insulin resistance induced by obesity. To determine whether the islet cell overgrowth is dependent on GH signaling, we studied the response of male GH[R.sup.-/-] mice to high-fat diet (HFD)-induced obesity. After 17 wk on a HFD, GH[R.sup.-/-] mice became more significantly obese than wild-type mice and exhibited increased [beta]-cell mass to a slightly higher extent. These data demonstrate that GH signaling is not required for compensatory islet growth. Thus, in both muscle insulin responsiveness and islet growth compensation, normal levels of GH signals do not seem to play a dominant role. gene-disrupted mice; insulin receptor; phosphorylation; [beta]-cell mass; high-fat diet doi: 10.1152/ajpendo.00378.2005

This study investigated whether relatively automatic evaluations of food differ between situations and between obese people and lean controls. These evaluations were assessed in the affective priming paradigm (APP)--a response latency based measure for associations. In Experiment I, we either focused participants (33 obese and 26 lean controls) on the palatability (restaurant condition) or on the healthiness (health condition) of food, prior to the APP. Independent of weight-status, relatively automatic evaluations of food were based on palatability in the restaurant condition, and on health in the health condition. So, the current focus of attention can shape the way foods are evaluated relatively automatically. In Experiment 2, craving was induced in participants (27 obese and 29 lean controls). Unexpectedly, the craving induction did not achieve its goal of focusing on the palatability of food in general, but just for low-fat foods, possibly because of the health-emphasizing environment a hospital. Interestingly, obese people showed a stronger palatability priming effect with increasing levels of initial craving. For normal weight controls the effect was in the same direction, but missed significance. In our environment, palatability of food may be too salient, and health may not be salient enough, influencing automatic food-evaluations. Keywords: Eating attitudes; Obesity; Affective priming paradigm; Automatic evaluation

Intakes of some macronutrients can comprise risk factors for life-style-related diseases such as obesity, hyperlipidemia, diabetes, hypertension, and atherosclerosis. In this study, we examined the effects in C57BL/6J mice of consuming excess fat or sucrose for a long period of time (55 wk). Another group of mice consumed a low-fat, low-sucrose (LL) diet. Mice fed the high-fat (HF) diet gained weight and developed hyperlipidemia and hyperleptinemia. At 25 wk, but not at 55 wk, hepatic glucose-6-phosphatase (G6Pase) activity of the mice fed the high sucrose (HS) diet was greater than that of mice fed the LL or HF diet. Those fed the HS diet were not obese and had greater hepatic lipogenic and gluconeogenic enzyme activities. The HF and HS diets resulted in different types of glucose intolerance. In an oral glucose tolerance test, mice fed the HF diet had a delay in the clearance of glucose compared with those fed the LL diet, perhaps due to the peripheral insulin resistance that resulted from higher levels of circulating free fatty acids. Feeding the HS diet for 55 wk induced hyperglycemia 10 min after oral glucose administration, although blood glucose declined rapidly after i.p. insulin injection. This finding suggests that the effects of chronic HS diet intake may be due to the reduction in early insulin secretion from pancreatic islets and the increase in sucrase activity in the small intestine. It is important to consider the effects of macronutrients in lean as well as obese mice to clarify the pathogenesis of the metabolic disorders. KEY WORDS: * high-fat * high-sucrose * glucose intolerance * obesity * lean

Five days of a high-fat diet while training, followed by 1 day of carbohydrate (CHO) restoration, increases rates of whole body fat oxidation and decreases CHO oxidation during aerobic cycling. The mechanisms responsible for these shifts in fuel oxidation are unknown but involve up- and downregulation of key regulatory enzymes in the pathways of skeletal muscle fat and CHO metabolism, respectively. This study measured muscle PDH and HSL activities before and after 20 min of cycling at 70% V[O.sub.2 peak] and 1 min of sprinting at 150% peak power output (PPO). Estimations of muscle glycogenolysis were made during the initial minute of exercise at 70% V[O.sub.2 peak] and during the 1-min sprint. Seven male cyclists undertook this exercise protocol on two occasions. For 5 days, subjects consumed in random order either a high-CHO (HCHO) diet (10.3 g*[kg.sup.-1]*[day.sup.-1] CHO, or ~70% of total energy intake) or an isoenergetic high-fat (FAT-adapt) diet (4.6 g*[kg.sup.-]*[day.sup.-1] FAT, or 67% of total energy) while undertaking supervised aerobic endurance training. On day 6 for both treatments, subjects ingested an HCHO diet and rested before their experimental trials on day 7. This CHO restoration resulted in similar resting glycogen contents (FAT-adapt 873 [+ or -] 121 vs. HCHO 868 [+ or -] 120 [micro]mol glucosyl units/g dry wt). However, the respiratory exchange ratio was lower during cycling at 70% V[O.sub.2 peak] in the FAT-adapt trial, which resulted in an ~45% increase and an ~30% decrease in fat and CHO oxidation, respectively. PDH activity was lower at rest and throughout exercise at 70% V[O.sub.2 peak] (1.69 [+ or -] 0.25 vs. 2.39 [+ or -] 0.19 mmol*kg wet [wt.sup.-1]*[min.sup.-1]) and the 1-min sprint in the FAT-adapt vs. the HCHO trial. Estimates of glycogenolysis during the 1st min of exercise at 70% V[O.sub.2 peak] and the 1-min sprint were also lower after FAT-adapt (9.1 [+ or -] 1.1 vs. 13.4 [+ or -] 2.1 and 37.3 [+ or -] 5.1 vs. 50.5 [+ or -] 2.7 glucosyl units*kg dry [wt.sup.-l]*[min.sup.-1]). HSL activity was ~20% higher (P = 0.12) during exercise at 70% V[O.sub.2 peak] after FAT-adapt. Results indicate that previously reported decreases in whole body CHO oxidation and increases in fat oxidation after the FAT-adapt protocol are a function of metabolic changes within skeletal muscle. The metabolic signals responsible for the shift in muscle substrate use during cycling at 70% V[O.sub.2 peak] remain unclear, but lower accumulation of free ADP and AMP after the FAT-adapt trial may be responsible for the decreased glycogenolysis and PDH activation during sprinting. skeletal muscle metabolism; pyruvate dehydrogenase; substrate phosphorylation; fat oxidation; carbohydrate oxidation

Changes in dietary macronutrient composition and/or central nervous system neuronal activity can underlie obesity and disturbed fuel homeostasis. We examined whether switching rats from a diet with high carbohydrate content (HC; i.e., regular chow) to diets with either high fat (HF) or high fat/high protein content at the expense of carbohydrates (LC-HF-HP) causes differential effects on body weight and glucose homeostasis that depend on the integrity of brain melanocortin (MC) signaling. In vehicle-treated rats, switching from HC to either HF or LC-HF-HP feeding caused similar reductions in food intake without alterations in body weight. A reduced caloric intake (-16% in HF and LC-HF-HP groups) required to maintain or increase body weight underlay these effects. Chronic third cerebroventricular infusion of the MC receptor antagonist SHU9119 (0.5 nmol/day) produced obesity and hyperphagia with an increased food efficiency again observed during HF (+ 19%) and LC-HF-HP (+33%) feeding. In this case, however, HF feeding exaggerated SHUg119-induced hyperphagia and weight gain relative to HC and LC-HF-HP feeding. Relative to vehicle-treated controls, SHU9119 treatment increased plasma insulin (2.8-4 fold), leptin (7.7-15 fold), and adiponectin levels (2.4-3.7 fold), but diet effects were only observed on plasma adiponectin (HC and LC-HFHP melanocortins; ketogenic diet; SHU9119; glucose tolerance

Byline: Igor Sukhotnik (1), A. Semih Gork (1), Min Chen (1), Robert A. Drongowski (1), Arnold G. Coran (1), Carroll M. Harmon (1) Keywords: Short bowel syndrome; Dietary lipid; Lipid absorption; Fatty acid uptake Abstract: Long chain fatty acids (LCFAs) appear to be powerful stimulants for small bowel adaptation in patients with short bowel syndrome (SBS). However, the dietary lipid content may alter intestinal lipid transport. The aim of this study was to investigate the effects of a high fat diet (HFD) on in vivo lipid absorption and molecular and cellular mechanisms of LCFAs uptake by the remaining bowel. Male Sprague-Dawley rats (240--280) were randomly assigned to one of three groups: sham rats fed normal chow (sham-NC), SBS rats fed NC (SBS-NC) and SBS rats fed HFD (SBS-HFD). SBS rats underwent a 75% small bowel resection. Rats were sacrificed on day 3 or 14. Body weight, fat intake and fat clearance (total fecal fat) were measured twice a week. Fat absorbability was calculated as intake minus clearance and was expressed as percent of intake. Total RNA from the mucosa of duodenum, jejunum and ileum was extracted using TRIZOL Reagent. Northern blot analysis was performed to determine FAT/CD36 mRNA levels. Enterocyte LCFA transport was measured on day 14. LCFA uptake was determined by measuring cellular [3H]-oleate uptake over time (4--120 s). Mean (+-SE) FAT/CD36 mRNA levels and oleate uptake kinetic parameters were analyzed using ANOVA. Fat absorbability diminished after bowel resection, suggesting fat malabsorption. Remaining bowel in SBS-NC rats responded by an increase in FAT/CD36 mRNA levels in the duodenum and ileum on day 3, and the duodenum and jejunum on day 14 compared to sham-NC animals, and was accompanied by an increase in enterocyte LCFA transport in all segments. Exposure to a HFD for 14 days resulted in significantly increased fat absorbability after 3 days compared to SBS-NC rats. However, FAT/CD36 mRNA levels (vs. SBS-NC) decreased in all segments on day 3. On day 14, FAT/CD36 mRNA levels were decreased in the duodenum and ileum and were accompanied by reduced oleate uptake by isolated enterocytes in the ileum (vs. SBS-NC). In a rat model of SBS, early high fat diet increased lipid absorptive capacity of the intestinal remnant as seen by increased fat absorbability. The main mechanisms of this effect may be an acceleration of structural intestinal adaptation resulting in an increased number of enterocytes. However, at molecular and cellular levels HFD decreased mucosal FAT/CD36 mRNA levels and oleic acid uptake by isolated enterocytes. Author Affiliation: (1) C.S. Mott Children's Hospital and University of Michigan Medical School, Ann Arbor, MI, USA Article History: Accepted Date: 10/12/2002 Online Date: 30/04/2003

Very low-carbohydrate (ketogenic) diets are popular yet little is known regarding the effects on serum biomarkers for cardiovascular disease (CVD). This study examined the effects of a 6-wk ketogenic diet on fasting and postprandial serum biomarkers in 20 normal-weight, normolipidemic men. Twelve men switched from their habitual diet (17% protein, 47% carbohydrate and 32% fat) to a ketogenic diet (30% protein, 8% carbohydrate and 61% fat) and eight control subjects consumed their habitual diet for 6 wk. Fasting blood lipids, insulin, LDL particle size, oxidized LDL and postprandial triacylglycerol (TAG) and insulin responses to a fat-rich meal were determined before and after treatment. There were significant decreases in fasting serum TAG (-33%), postprandial lipemia after a fat-rich meal (-29%), and fasting serum insulin concentrations (-34%) after men consumed the ketogenic diet. Fasting serum total and LDL cholesterol and oxidized LDL were unaffected and HDL cholesterol tended to increase with the ketogenic diet (+11.5%; P = 0.066). In subjects with a predominance of small LDL particles pattern B, there were significant increases in mean and peak LDL particle diameter and the percentage of LDL-1 after the ketogenic diet. There were no significant changes in blood lipids in the control group. To our knowledge this is the first study to document the effects of a ketogenic diet on fasting and postprandial CVD biomarkers independent of weight loss. The results suggest that a short-term ketogenic diet does not have a deleterious effect on CVD risk profile and may improve the lipid disorders characteristic of atherogenic dyslipidemia. KEY WORDS: * triglycerides * postprandial lipemia * lipoprotein subclasses

Research was conducted to examine the effect of acetate in fasting piglets infused with hexanoate. Another objective of the study is to explore the possibility that mitochondrial acetogenesis increases as mitochondrial fatty acid beta-oxidation rises in-vivo. Results demonstrate comparatively elevated plasma acetate and a basal acetate which suggest that significant production/utilization are consistent with important physiological role for acetate compared to ketone bodies in piglets.

A study was conducted to examine the activity-based anorexia could be prevented with palatable foods. Findings suggest that certain palatable diets affect the development of activity-based anorexia.

Eriocitrin, the main flavonoid in lemon fruit was investigated for its lowering effect on serum and hepatic lipids in high fat and high-cholesterol fed rats. It was found that eriocitrin has a lowering effect for total cholesterol, VLDL+LDL, triglyceride in high-fat and high-cholesterol fed rats and lowering effect of eriocitrin is caused by a decrease in VLDL+LDL.