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BACKGROUND/OBJECTIVES: Intake of food or fluid distends the stomach and triggers mechanoreceptors and vagal afferents. Wall stretch and tension produces a feeling of fullness. Duodenal infusion studies assessing gastric sensitivity by barostat have shown that the products of fat digestion have a greater effect on the sensation of fullness and also dyspeptic symptoms than carbohydrates. We tested here the hypothesis that fat and carbohydrate have different effects on gastric sensation under physiological conditions using non-invasive magnetic resonance imaging (MRI) to measure gastric volumes. SUBJECTS/METHODS: Thirteen healthy subjects received a rice pudding test meal with added fat or added carbohydrate on two separate occasions and underwent serial postprandial MRI scans for 4.5 h. Fullness was assessed on a 100-mm visual analogue scale. RESULTS: Gastric half emptying time was significantly slower for the high-carbohydrate meal than for the high-fat meal, P = 0.0327. Fullness significantly correlated with gastric volumes for both meals; however, the change from baseline in fullness scores was higher for the high-fat meal for any given change in stomach volume (P = 0.0147), despite the lower energy content and faster gastric emptying of the high-fat meal. CONCLUSIONS: Total gastric volume correlates positively and linearly with postprandial fullness and ingestion of a high-fat meal increases this sensation compared with high-carbohydrate meal. These findings can be of clinical interest in patients presenting with postprandial dyspepsia whereby manipulating gastric sensitivity by dietary intervention may help to control digestive sensations. European Journal of Clinical Nutrition (2015) 69, 380-384; doi: 10.1038/ejcn.2014.194; published online 17 September 2014, INTRODUCTION The main functions of the stomach are to receive and accommodate food, break it down chemically and mechanically and deliver the digesta to the small intestine. This process is [...]

ABSTRACT The aim of this study was to determine whether the Rehmannia glutinosa oligosaccharides (ROS) ameliorate the impaired glucose metabolism and the potential mechanism in chronic stress rats fed with [...]

The bacteria that inhabit the rodent gut promote insulin secretion and food intake by activating the parasympathetic nervous system--a hitherto unknown mode of action for this multifaceted microbiota. See Article [...]

BACKGROUND/OBJECTIVES: Recent work suggests that macronutrients are pro- inflammatory and promote oxidative stress. Reports of postprandial regulation of total adiponectin have been mixed, and there is limited information regarding postprandial changes in high molecular weight (HMW) adiponectin. The aim of this study was to assess the effect of a standardised high-fat meal on metabolic variables, adiponectin (total and HMW), and markers of inflammation and oxidative stress in: (i) lean, (ii) obese non-diabetic and (iii) men with type 2 diabetes mellitus (T2DM). SUBJECTS/METHODS: Male subjects: lean (n = 10), obese (n = 10) and T2DM (n = 10) were studied for 6 h following both a high-fat meal and water control. Metabolic variables (glucose, insulin, triglycerides), inflammatory markers (interleukin-6 (IL6), tumour necrosis factor (TNF)α, high-sensitivity C-reactive protein (hsCRP), nuclear factor (NF)kB expression in peripheral blood mononuclear cells (p65)), indicators of oxidative stress (oxidised low density lipoprotein (oxLDL), protein carbonyl) and adiponectin (total and HMW) were measured. RESULTS: No significant changes in TNFα, p65, oxLDL or protein carbonyl concentrations were observed. Overall, postprandial IL6 decreased in subjects with T2DM but increased in lean subjects, whereas hsCRP decreased in the lean cohort and increased in obese subjects. There was no overall postprandial change in total or HMW adiponectin in any group. Total adiponectin concentrations changed over time following the water control, and the response was significantly different in lean subjects compared with subjects with T2DM (P = 0.04). CONCLUSIONS: No consistent significant postprandial inflammation, oxidative stress or regulation of adiponectin was observed in this study. Findings from the water control suggest differential basal regulation of total adiponectin in T2DM compared with lean controls. European Journal of Clinical Nutrition (2013) 67, 377- 384; doi: 10.1038/ejcn.2013.49; published online 6 March 2013 Keywords: postprandial dysmetabolism; inflammation; oxidative stress; adiponectin; obesity; type 2 diabetes, INTRODUCTION A number of studies have identified an inflammatory response in the postprandial period. (1-5) Similarly, markers of oxidative stress are elevated following glucose, (2,4,5) fat (4,6) and mixed-meal challenge. [...]

This study tested the hypothesis that exercise training would prevent the development of diabetes-induced cardiac dysfunction and altered expression of sarcoplasmic reticulum [Ca.sup.2+]-transport proteins in the low-dose streptozotocin-induced diabetic rats fed a high-fat diet (HFD+STZ). Male Sprague-Dawley rats (4 weeks old; 125-150 g) were made diabetic using a highfat diet (40% fat, w/w) and a low-dose of streptozotocin (35 mg-(kg body mass)-1) by intravenous injection. Diabetic animals were divided among a sedentary group (Sed+HFD+STZ) or an exercise-trained group (Ex+HFD+STZ) that accumulated 3554 ±338 m*[day.sup.-1] of voluntary wheel running (mean ± SE). Sedentary animals fed a low-fat diet served as the control (Sed+LFD). Oral glucose tolerance was impaired in the sedentary diabetic group (1179 ±29; area under the curve (a.u.c.)) compared with that in the sedentary control animals (1447 ± 42 a.u.c.). Although left ventricular systolic function was unchanged by diabetes, impaired E/A ratios (i.e., diastolic function) and rates of pressure decay (-dP/dt) indicated the presence of diastolic dysfunction. Diabetes also reduced SERCA2a protein content and maximal SERCA2a activity ([V.sub.max]) by 21% and 32%, respectively. In contrast, the change in each parameter was attenuated by exercise training. Based on these data, it appears that exercise training prevented the development of diabetic cardiomyopathy and the dysregulation of sarcoplasmic reticulum protein content in an inducible animal model of type 2 diabetes. Key words: physical activity, exercise training, diabetes, cardiac dysfunction, echocardiography, diastolic dysfunction, SERCA, ryanodine receptor, phospholamban, calcium ([Ca.sup.2+]) handling, high-fat diet. Cette etude visait a verifier l'hypothese que l'exercice previendrait le developpement de la dysfonction cardiaque et la modification de l'expression de proteines de transport du [Ca.sup.2+] du reticulum sarcoplasmique induits par le diabete, chez des rats soumis a une diete riche en gras traites a une faible dose de streptozotocine (DRG+STZ). Des rats males Sprague-Dawley (ages de 4 semaines ; 125-150 g) ont ete rendus diabetiques par une diete riche en gras (40%) et l'injection d'une faible dose de streptozotocine (35 mg*[(kg de poids corporel).sup.-1], i.v.). Les animaux diabetiques ont ete repartis en groupes sedentaire (Sed+DRG+STZ) ou soumis a l'exercice (Ex+DRG+STZ) dont les animaux ont couru de maniere volontaire une distance de 3554 [+ ou -] 338 m*[jour.sup.-1] sur une roue d'entrainement (moyenne [+ ou -] ES). Des animaux sedentaires soumis a une diete faible en gras ont servi de controle (Sed+DFG). La tolerance au glucose par voie orale etait affectee chez les animaux diabetiques sedentaires (aire sous la courbe (a.s.c.), 1179 [+ ou -] 29) comparativement au groupe controle sedentaire (1447 [+ ou -] 42 a.s.c.). Meme si la fonction diastolique du ventricule gauche n'etait pas modifiee par le diabete, les rapports E/A et les taux de diminution de pression (-dP/dt) changes indiquaient la presence d'une dysfonction diastolique. Le diabete reduisait aussi le contenu en SERCA2a et l'activite maximale de SERCA2a ([V.sub.max]) de 21 % et 32 % respectivement. Par contre, les changements observes dans chaque parametre etaient attenues par l'exercice. Selon ces donnees, il semble que l'exercice previenne le developpement de la cardiomyopathie diabetique et la deregulation du contenu proteique du reticulum sarcoplasmique chez un modele animal de diabete de type 2 inductible. [Traduit par la Redaction] Mots-cles : activite physique, exercice, diabete, dysfonction cardiaque, echocardiographie, dysfonction diastolique, SERCA, recepteur ryanodine, phospholamban, prise en charge du [Ca.sup.2+], diete riche en gras., Introduction Diabetes affects an estimated 246 million people worldwide of which 2 million are Canadians (Lipscombe and Hux 2007). Cardiovascular disease is the most common complication of diabetes (Laakso 1999; [...]

We have measured the responses to endurance exercise training on body composition and glucose regulation, as well as cardiovascular and liver structure and function in rats fed a high carbohydrate and high fat (HCHF) diet as a model of human metabolic syndrome. Male Wistar rats (9-10 weeks old) were randomly allocated into corn starch (CS) or HCHF diet groups for 16 weeks; half of each group were exercised on a treadmill for 20, 25, and then 30 min/day, 5 days/week, during the last 8 weeks of the protocol. Metabolic, cardiovascular, and liver parameters were monitored. The HCHF diet induced symptoms of metabolic syndrome, including obesity, dyslipidemia, impaired glucose tolerance, and increased systolic blood pressure associated with the development of cardiovascular remodeling and nonalcoholic steatohepatitis. Exercise in HCHF rats decreased body mass, abdominal fat pads and circumference, blood glucose concentrations, plasma lipid profiles, systolic blood pressure, left ventricular diastolic stiffness, collagen deposition and inflammatory cell infiltration in the left ventricle, improved aortic contractile and relaxation responses, and decreased liver mass and hepatic fat accumulation. This study demonstrates that endurance exercise is effective in this rat model of diet-induced metabolic syndrome in improving body composition and glucose regulation, as well as cardiovascular and liver structure and function. Key words: body composition, glucose tolerance, cardiac remodeling, endothelial dysfunction, liver function. Nous avons mesure les reponses a un entrainement d'endurance sur la composition corporelle, la regulation du glucose, et la structure et la fonction des systemes cardiovasculaires et hepatiques de rats nourris avec une diete riche en glucides et en gras (RGG) utilises comme modele du syndrome metabolique chez l'humain. Des rats Wistar males (ages de 9 a 10 semaines) ont ete distribues au hasard en groupes nourris a l'amidon de mais (AM) ou avec une diete RGG pendant 16 semaines ; la moitie de chaque groupe a ete entrainee sur un tapis roulant pendant 20, 25, puis 30 minutes/jour, 5 jours par semaine, durant les 8 dernieres semaines du protocole. Les parametres metaboliques, cardiovasculaires et hepatiques ont ete suivis. La diete RGG induisait les symptomes du syndrome metabolique incluant l'obesite, la dyslipemie, la reduction de la tolerance au glucose et l'augmentation de la pression sanguine systolique, associees au developpement du remodelage cardiovasculaire et a la steatohepatite non alcoolique. L'exercice diminuait le poids corporel des rats du groupe RGG, ainsi que l'adiposite et la circonference de l'abdomen, les concentrations de glucose sanguin, les profiles de lipides plasmatiques, la pression sanguine systolique, la rigidite diastolique de ventricule gauche, le depot de collagene et l'infiltration du ventricule gauche par les cellules inflammatoires ; il ameliorait en outre la contraction et la relaxation de l'aorte et diminuait le poids du foie et l'accumulation de graisses hepatiques. Cette etude demontre que l'exercice d'endurance est efficace dans ce modele de syndrome metabolique induit par la diete chez le rat en ameliorant la composition corporelle, la regulation du glucose, et la structure et la fonction des systemes cardiovasculaires et hepatiques. Mots-cles : composition corporelle, tolerance au glucose, remodelage cardiaque, dysfonction endotheliale, fonction hepatique. [Traduit par la Redaction], Introduction Metabolic syndrome comprises cardiovascular and metabolic risk factors such as abdominal obesity, impaired glucose regulation, insulin resistance, hypertension, atherogenic dyslipidemia, and proinflammatory state (Moller and Kaufman 2005). This syndrome [...]

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 tested whether a high-fat diet (HFD) impairs the survival of probiotics in mice. In Expt. 1, after feeding either a HFD (62.7% energy) or a normal-fat diet (NFD; 11.1% energy) for 2 d, C57BL/6 mice were i.g. administered Lactobacillus plantarum No. 14. Fecal recovery of viable L. plantarum was significantly decreased 99% by the HFD compared with the NFD. Total bile acid concentrations in the small intestine and cecum were significantly higher (1.5- and 2.2-fold of NFD, respectively) in mice fed HFD than in those fed NFD. Cholic acid and deoxycholic acid significantly reduced the viability of L. plantarum No. 14 in culture experiments. In Expt. 2, after feeding HFD for 2 d, simultaneous administration of inulin (10 mg) with L. plantarum No. 14 significantly increased (100-fold of that without inulin) the fecal recovery of viable L. plantarum. Inulin administration did not alter intestinal bile acid concentrations. In Expt. 3, after feeding HFD for 2 d, mice were i.g. administered either inulin (10 mg) or vehicle and, after 6 h, cecal contents were subjected to culture experiments. Growth of L. plantarum No. 14 was significantly higher in the cecal contents of inulin-administered mice than vehicle- administered mice. Inulin supplementation to cecal contents of vehicle-administered mice significantly enhanced the growth of L. plantarum No. 14. We propose that HFD impairs the survival of probiotics in the gut due to increased bile acid stress and that simultaneous administration of inulin prolongs the survival of probiotics in mice fed HFD. J. Nutr. 140: 1963-1969, 2010. doi: 10.3945/jn.110.128082.

After loss of intestinal surface area, the remaining bowel undergoes a morphometric and functional adaptive response. Enterocytic expression of the transcriptional coregulator tetradecanoyl phorbol acetate induced sequence 7 (Tis7) is markedly increased in a murine model of intestinal adaptation. Mice overexpressing Tis7 in intestine have greater triglyceride absorption and weight gain when fed a high-fat diet (42% energy) than their wild-type (WT) littermates fed the same diet. These and other data suggest that Tis7 has a unique role in nutrient absorptive and metabolic adaptation. Herein, male [Tis7.sup.-/-] and WT mice were fed a high-fat diet (42% energy) for 8 wk. Weight was monitored and metabolic analyses and hepatic and intestinal lipid concentrations were compared after 8 wk. Intestinal lipid absorption and metabolism studies and intestinal resection surgeries were performed in separate groups of [Tis7.sup.-/-] and WT mice. At 8 wk, weight gain was less and jejunal mucosal and hepatic triglyceride and cholesterol concentrations were lower in [Tis7.sup.-/-] mice than in the WT controls. Following corn oil gavage, serum cholesterol, triglyceride, and FFA concentrations were lower in the [Tis7.sup.-/-] mice than in the WT mice. Incorporation of oral [sup.3][H] triolein into intestinal mucosal cholesterol ester and FFA was less in [Tis7.sup.-/-] compared with WT mice. Following resection, crypt cell proliferation rates and villus heights were lower in [Tis7.sup.-/-] than in VVT mice, indicating a blunted adaptive response. Our results suggest a novel physiologic function for Tis7 in the gut as a global regulator of lipid absorption and metabolism and epithelial cell proliferation. J. Nutr. 140: 1907-1914, 2010. doi: 10.3945/jn.110.127084.

Consumption of diets high in fat and calories leads to hyperphagia and obesity, which is associated with chronic 'low-grade' systemic inflammation. Ingestion of a high-fat diet alters the gut microbiota, pointing to a possible role in the development of obesity. The present study used Sprague-Dawley rats that, when fed a high-fat diet, exhibit either an obesity-prone (DIO-P) or obesity-resistant (DIO-R) phenotype, to determine whether changes in gut epithelial function and microbiota are diet or obese associated. Food intake and body weight were monitored daily in rats maintained on either low- or high-fat diets. After 8 or 12 wk, tissue was removed to determine adiposity and gut epithelial function and to analyze the gut microbiota using PCR. DIO-P but not DIO-R rats exhibit an increase in toll-like receptor (TLR4) activation associated with ileal inflammation and a decrease in intestinal alkaline phosphatase, a luminal enzyme that detoxifies lipopolysaccharide (LPS). Intestinal permeability and plasma LPS were increased together with phosphorylation of myosin light chain and localization of occludin in the cytoplasm of epithelial cells. Measurement of bacterial 16S rRNA showed a decrease in total bacterial density and an increase in the relative proportion of Bacteroidales and Clostridiales orders in high-fat-fed rats regardless of phenotype; an increase in Enterobacteriales was seen in the microbiota of DIO-P rats only. Consumption of a high-fat diet induces changes in the gut microbiota, but it is the development of inflammation that is associated with the appearance of hyperphagia and an obese phenotype. diet-induced obesity; endotoxin; toll-like receptor-4; Enterobacteriales; Bacteroidales; Clostridiales doi: 10.1152/ajpgi.00098.2010.

Glucagon-like peptide-1 (GLP-1) improves insulin sensitivity in humans and rodents. It is currently unknown to what extent the (metabolic) effects of GLP-1 treatment are mediated by central GLP-1 receptors. We studied the impact of central GLP-1 receptor (GLP-1R) antagonism on the metabolic effects of peripheral GLP-1 administration in mice. High-fatfed insulin-resistant C57B1/6 mice were treated with continuous subcutaneous infusion of GLP-1 or saline (PBS) for 2 wk, whereas the GLP-1R antagonist exendin-9 (EX-9) and cerebrospinal fluid (CSF) were simultaneously infused in the left lateral cerebral ventricle (icy). Glucose and glycerol turnover were determined during a hyperinsulinemic euglycemic clamp. VLDL-triglyceride (VLDL-TG) production was determined in hyperinsulinemic conditions. Our data show that the rate of glucose infusion necessary to maintain euglycemia was significantly increased by GLP-1. Simultaneous icv infusion of EX-9 diminished this effect by 62%. The capacities of insulin to stimulate glucose disposal and inhibit glucose production were reinforced by GLP-1. Simultaneous icv infusion of EX-9 significantly diminished the latter effect. Central GLP-1R antagonism alone did not affect glucose metabolism. Also, GLP-1 treatment reinforced the inhibitory action of insulin on VLDL-TG production. In conclusion, peripheral administration of GLP-1 reinforces the ability of insulin to suppress endogenous glucose and VLDL-TG production (but not lipolysis) and boosts its capacity to stimulate glucose disposal in high-fat-fed C57B1/6 mice. Activation of central GLP-1Rs contributes substantially to the inhibition of endogenous glucose production by GLP-1 treatment in this animal model. glucagon-like peptide-1; gut hormone; exendin-9; central receptor; hyperinsulinemic euglycemic clamp; insulin-resistant animal model doi: 10.1152/ajpendo.00191.2010.

The Rendement Napole (RN) genotype widely exists in Hampshire pigs. Recently, RN gene was identified as a R200Q mutation in AMP-activated protein kinase (AMPK) [gamma]3 subunit. The effect of RN genotype on the growth performance of animals and the underlying mechanisms remain controversial. Using transgenic mice carrying an analogous R225Q mutation, the objective of this study was to study the role of RN gene in the growth performance of animals at different energy levels. Wild-type (WT) mice and those with the RN mutation were assigned to 4 groups: 1) WT plus normal diet, 2) RN plus normal diet, 3) WT plus high-energy diet, and 4) RN plus high-energy diet. Mice were weaned at 21 d old and fed the trial diets for 1 mo and then killed for carcass measurements. The pH of postmortem muscle from RN mice was less (P < 0.01) than that from WT mice. No difference in growth performance was observed when mice were fed a normal diet. When fed a high-energy diet, RN mice shouted a greater fat accumulation (WT vs. RN, 1.11 vs. 1.63 g for gonadal fat and 1.40 vs. 1.84 g for subcutaneous fat; P < 0.05). Muscle weight was also increased (WT vs. RN, 0.27 vs. 0.30 g for gastrocnemius muscle; P < 0.05). The food consumption was greater in RN compared with WT mice (2.95 vs. 2.49 g; P < 0.05). The AMPK content and its downstream target, acetyl-CoA carboxylase (ACC), content were greater in RN mice (P < 0.05). The phosphorylation of ACC at Ser 79, a site exclusively phosphorylated by AMPK, was increased (P < 0.05), showing greater AMPK activity in RN mouse muscle. No difference in muscle fiber composition and mitochondrial content was observed between WT and RN mice. High fat diet downregulates protein kinase B but upregulates extracellular signal-regulated kinase signaling. In conclusion, the R225Q mutation has no major effect on the growth performance of animals fed a normal diet; a high-energy diet increased fatness in RN mice, likely due to their greater consumption of feed compared with WT mice. Key words: AMP-activated protein kinase, energy, fat accumulation, growth performance, muscle, Rendement Napole gene doi: 10.2527/jas.2009-2376

Intracerebroventricular insulin decreases food intake (FI). The central bed nucleus of the amygdala (CeA), as other regions of the brain regulating feeding behavior, expresses insulin receptors. Our objectives were to show an insulin anorectic response in the amygdala, study the effect of high-fat diets on this response, and map the neural network activated by CeA insulin using c-Fos immunohistochemistry. Sprague-Dawley (SD) rats fitted with unilateral CeA cannulas were adapted to a low-fat (LFD) diet before they were fed a high-fat diet (HFD). Their feeding response to CeA saline or insulin (8 mU) was tested after 24 h, 72 h, or 7 days of being on a HFD. In a second experiment, SD rats were fed the HFD for 3, 7, or 49 days and were then refed with the LFD. They were tested for their insulin response before and after an HFD and every 3 days for the following weeks. Insulin tolerance tests were performed in a parallel group of rats. The CeA insulin stimulation c-Fos expression was studied to identify the distribution of activated neuronal populations. Feeding an HFD for 72 h or more induced a CeA, but not peripheral, insulin resistance, which was slowly reversed by LFD refeeding. The duration of HFD feeding determined the time frame for reversal of the insulin resistance. CeA insulin increased c-Fos in multiple brain regions, including the arcuate nucleus/paraventricular nucleus region of the hypothalamus. We conclude that the amygdala may be an important site for insulin regulation of food intake and may have a significant role in determining susceptibility to HFD-induced obesity. rat; food intake; central insulin sensitivity; limbic system doi: 10.1152/ajpregu.00252.2009.

Caloric restriction (CR) and metabolic glucoprivation affect spontaneous physical activity (SPA), but it's unknown whether these treatments similarly affect SPA in selectively bred obesity-prone (OP) and -resistant (OR) rats. OR rats have greater basal SPA and are more responsive to treatments that modulate SPA, such as orexin A administration. We hypothesized that OR rats would be more sensitive to other treatments modulating SPA. To test this, continuous 24-h SPA was measured before and during acute (24 h) and chronic (8 wk) CR in OR, OP, and Sprague-Dawley rats. Pharmacological glucoprivation was produced by injection of 2-deoxyglucose (2-DG), and SPA was measured 5 h postinjection. Acute CR increased SPA in all groups; however, the effect was dependent on the index of SPA and time interval during the 24-h time period. In contrast to OR rats, chronic CR increased distance traveled, ambulatory episodes, and time spent in ambulation and stereotypy during the time interval preceding anticipation of food in OP and Sprague-Dawley rats. Although the effects of 2-DG treatment on SPA were minimal, OR rats had significantly greater SPA than OP and Sprague-Dawley rats independent of treatment. That chronic CR failed to result in significant changes in SPA in OR rats suggests that these rats may be especially unresponsive to treatments modulating feeding. This insensitivity coupled with elevated basal SPA levels may in part mediate phenotypic traits of lean rats. food deprivation; locomotor activity; diet-induced obesity

Intestinal alkaline phosphatase (IAP) is a brush-border membrane ectoenzyme (BBM-IAP) that is released into the lumen (L-IAP) after a high-fat diet. We examined the effects of oil feeding and the addition of mixed-lipid micelles on the formation of L-IAP in oil-fed rat intestine, Caco-2 cell monolayers, and mouse intestinal loops. We localized IAP in the duodenum of rats fed corn oil using fluorescence microscopy with enzyme-labeled fluorescence-97 as substrate. Four hours after oil feeding, L-IAP increased ~10-fold accompanied by the loss of BBM-IAP, consistent with BBM-IAP release. Rat IAP isozyme mRNAs progressively increased 4-6 h after oil feeding, followed by the increase of IAP activity in the subapical location at 6 h, consistent with the restoration of IAP protein. Postprandial lipid-micelle components, sodium taurocholate with or without oleic acid, mono-oleylglycerol, cholesterol, or lysophosphatidylcholine (lysoPC) were applied singly or as mixed-lipid micelles to the apical surface of polarized Caco-2 cell monolayers. LysoPC increased L-IAP >10-fold over basal release. LysoPC released lAP into the apical medium more than other intestinal brush-border enzymes, 5'-nucleotidase, sucrase, aminopeptidase N, and lactase, without comparable lactate dehydrogenase release or cell injury. LysoPC increased human IAP mRNA levels by 1.5-fold in Caco-2 cells. Luminally applied lysoPC also increased release of IAP preferentially in mouse intestinal loops. These data show that lysoPC accelerates the formation of L-IAP from BBM-IAP, followed by enhanced IAP synthesis, suggesting the role that lysoPC might play in the turnover of brush-border proteins. Caco-2 cells; lipid absorption; small intestine; enzyme-labeled fluorescence-97

Elevated plasma free fatty acids (FFA) cause insulin resistance and are thought to play a key role in mediating insulin resistance in patients with the metabolic syndrome (MTS) and type 2 diabetes mellitus (DM). Two experimental models used to study the mechanisms responsible for insulin resistance in patients are high-fat diet-fed rodents and administration of triglycerides and heparin to raise plasma FFA. As evidence that insulin resistance in high-fat diet-fed rats is due to high FFA, it has been reported that the insulin resistance is rapidly reversed by an overnight fast, a high-glucose meal, and an exercise bout. If true, these findings would invalidate the high-fat diet-fed rodent as a model for MTS or type 2 DM, because insulin resistance is not rapidly reversed by these treatments in patients. The purpose of this study was to determine whether diet-induced insulin resistance is, in fact, rapidly reversible. Incubation of muscles in vitro rapidly reversed insulin resistance induced by administration of triglycerides and heparin, but not by a high-fat diet. An overnight fast and a high-glucose meal were followed by a large increase in insulin-stimulated muscle glucose transport. However, these are adaptive responses, rather than reversals of insulin resistance, because they also occurred in muscles of insulin-sensitive, chow-fed control rats. Our results show that insulin resistance induced by high FFA, i.e., Randle glucose-fatty acid cycle, is transient. In contrast, the insulin resistance induced by a high-fat diet does not reverse rapidly. free fatty acids; glucose-fatty acid cycle; high-fat diet; insulin sensitivity

Brown adipose tissue activity dissipates energy as heat, and there is evidence that lack of the retinoblastoma protein (pRb) may favor the development of the brown adipocyte phenotype in adipose cells. In this work we assessed the impact of germ line haploinsufficiency of the pRb gene (Rb) on the response to high-fat diet feeding in mice. [Rb.sup.+/-] mice had body weight and adiposity indistinguishable from that of wild-type ([Rb.sup.+/+]) littermates when maintained on a standard diet, yet they gained less body weight and body fat after long-term high-fat diet feeding coupled with reduced feed efficiency and increased rectal temperature. Rb haploinsufficiency ameliorated insulin resistance and hepatosteatosis after high-fat diet in male mice, in which these disturbances were more marked than in females. Compared with wild-type littermates, [Rb.sup.+/-] mice fed a high-fat diet displayed higher expression of peroxisome proliferator-activated receptor (PPAR)[gamma] as well as of genes involved in mitochondrial function, cAMP sensitivity, brown adipocyte determination, and tissue vascularization in white adipose tissue depots. Furthermore, [Rb.sup.+/-] mice exhibited signs of enhanced activation of brown adipose tissue and higher expression levels of PPAR[alpha] in liver and of PPAR[delta] in skeletal muscle, suggestive of an increased capability for fatty acid oxidation in these tissues. These findings support a role for pRb in modulating whole body energy metabolism and the plasticity of the adipose tissues in vivo and constitute first evidence that partial deficiency in the Rb gene protects against the development of obesity and associated metabolic disturbances. brown adipose tissue; white adipose tissue; energy metabolism; genetic animal model

Skeletal muscle [Na.sup.+]-[K.sup.+]-ATPase plays a central role in the clearance of [K.sup.+] from the extracellular fluid, therefore maintaining blood [[K.sup.+]]. [Na.sup.+]-[K.sup.+]-ATPase activity in peripheral tissue is impaired in insulin resistant states. We determined effects of high-fat diet (HFD) and exercise training (ET) on skeletal muscle [Na.sup.+]-[K.sup.+]-ATPase subunit expression and insulin-stimulated translocation. Skeletal muscle expression of [Na.sup.+]-[K.sup.+]-ATPase isoforms and transcription factor DNA binding was determined before or after 5 days of swim training in Wistar rats fed chow or HFD for 4 or 12 wk. Skeletal muscle insulin resistance was observed after 12 wk of HFD. [Na.sup.+]-[K.sup.+]-ATPase [[alpha].sub.1]-subunit protein expression was increased 1.6-fold (P < 0.05), whereas [[alpha].sub.2]- and [[beta].sub.1]-subunits and protein expression were decreased twofold (P < 0.01) in parallel with decrease in plasma membrane [Na.sup.+]-[K.sup.+]-ATPase activity after 4 wk of HFD. Exercise training restored [[alpha].sub.1]-, [[alpha].sub.2]-, and [[beta].sub.1]-subunit expression and [Na.sup.+]-[K.sup.+]-ATPase activity to control levels and reduced [[beta].sub.2]-subunit expression 2.2-fold (P < 0.05). DNA binding activity of the [[alpha].sub.1]-subunit-regulating transcription factor ZEB (AREB6) and [[alpha].sub.1] mRNA expression were increased after HFD and restored by ET. DNA binding activity of Sp-1, a transcription factor involved in the regulation of [[alpha].sub.2]- and [[beta].sub.1]-subunit expression, was decreased after HFD. ET increased phosphorylation of the [Na.sup.+]-[K.sup.+]-ATPase regulatory protein phospholemman. Phospholemman mRNA and protein expression were increased after HFD and restored to control levels after ET. Insulin-stimulated translocation of the [[alpha].sub.2]-subunit to plasma membrane was impaired by HFD, whereas [[alpha].sub.1]-subunit translocation remained unchanged. Alterations in sodium pump function precede the development of skeletal muscle insulin resistance. Disturbances in skeletal muscle [Na.sup.+]-[K.sup.+]-ATPase regulation, particularly the [[alpha].sub.2]-subunit, may contribute to impaired ion homeostasis in insulin-resistant states such as obesity and type 2 diabetes. phospholemman; protein expression; transcription factors; sodium pump

Protein tyrosine phosphatase 1B (PTP1B) contributes to leptin resistance by inhibiting intracellular leptin receptor signaling. Mice with whole body or neuron-specific deletion of PTP1B are hypersensitive to leptin and resistant to diet-induced obesity. Here we report a significant increase in PTP1B protein levels in the mediobasal hypothalamus (P = 0.003) and a concomitant reduction in leptin sensitivity following 28 days of high-fat (HF) feeding in rats. A significant increase in PTP1B mRNA levels was also observed in rats chronically infused with leptin (3 [micro]g/day icv) for 14 days (P = 0.01) and in leptin-deficient ob/ob mice infused with leptin (5 [micro]g/day sc for 14 days; P = 0.003). When saline-infused ob/ob mice were placed on a HF diet for 14 days, an increase in hypothalamic PTP1B mRNA expression was detected (P = 0.001) despite the absence of circulating leptin. In addition, although ob/ob mice were much more sensitive to leptin on a low-fat (LF) diet, a reduction in this sensitivity was still observed following exposure to a HF diet. Taken together, these data indicate that hypothalamic PTP1B is specifically increased during HF diet-induced leptin resistance. This increase in PTP1B is due in part to chronic hyperleptinemia, suggesting that hyperleptinemia is one mechanism contributing to the development of leptin resistance. However, these data also indicate that leptin is not required for the increase in hypothalamic PTP1B or the development of leptin resistance. Therefore, additional, leptin-independent mechanisms must exist that increase hypothalamic PTP1B and contribute to leptin resistance. high-fat diet; food intake; protein tyrosine phosphatase 1B

Interleukin-6 (IL-6) is systemically elevated in obesity and is a predictive factor to develop type 2 diabetes. Pancreatic islet pathology in type 2 diabetes is characterized by reduced [beta]-cell function and mass, an increased proportion of [alpha]-cells relative to [beta]-cells, and [alpha]-cell dysfunction. Here we show that the a cell is a primary target of IL-6 actions. Beginning with investigating the tissue-specific expression pattern of the IL-6 receptor (IL-6R) in both mice and rats, we find the highest expression of the IL-6R in the endocrine pancreas, with highest expression on the [alpha]-cell. The islet IL-6R is functional, and IL-6 acutely regulates both pro-glucagon mRNA and glucagon secretion in mouse and human islets, with no acute effect on insulin secretion. Furthermore, IL-6 stimulates [alpha]-cell proliferation, prevents apoptosis due to metabolic stress, and regulates [alpha]-cell mass in vivo. Using IL-6 KO mice fed a high-fat diet, we find that IL-6 is necessary for high-fat diet-induced increased [alpha]-cell mass, an effect that occurs early in response to diet change. Further, after high-fat diet feeding, IL-6 KO mice without expansion of [alpha]-cell mass display decreased fasting glucagon levels. However, despite these [alpha]-cell effects, high-fat feeding of IL-6 KO mice results in increased fed glycemia due to impaired insulin secretion, with unchanged insulin sensitivity and similar body weights. Thus, we conclude that IL-6 is necessary for the expansion of pancreatic [alpha]-cell mass in response to high-fat diet feeding, and we suggest that this expansion may be needed for functional [beta]-cell compensation to increased metabolic demand. alpha-cell mass | beta-cell function | high-fat diet | pancreatic islet

Chronic consumption of high-fat or -carbohydrate diets is associated with the development of obesity; however, it is not well established whether dietary protein plays a role in the development of abnormalities of lipid metabolism that occur during obesity. To determine the effect of different types of protein during diet-induced obesity on hepatic and adipocyte lipid metabolism, rats were fed casein (CAS) or soy (SOY) protein diets with 5% fat or high-fat diets with 25% fat (HF-CAS and HF-SOY) for 180 d. Rats fed soy diets had lower hepatic sterol regulatory element binding protein-1 (SREBP-1) expression and higher SREBP-2 expression than those fed casein diets, leading to less hepatic lipid deposition. On the other hand, long-term HF-SOY consumption prevented hyperleptinemia in comparison with rats fed HF-CAS. Rats fed soy protein diet showed higher adipocyte perilipin mRNA expression and smaller adipocyte area than those fed casein diets, which was associated with a lower body fat content. Furthermore, the lipid droplet area in brown adipose tissue was significantly lower in rats fed soy diets than in those fed casein diets and it was associated with higher uncoupling protein1 (UCP-1) expression. As a result, rats fed the soy diets gained less weight than those fed the casein diets, in part due to an increase in the thermogenic capacity mediated by UCP-1. These results suggest that the type of protein consumed and the presence of fat in the diet modulate lipid metabolism in adipose tissue and liver.

Increasing evidence indicates that replicative senescence and premature endothelial senescence could contribute to endothelial dysfunction. This study aims at testing the hypothesis that a high-fat diet may lead to premature vascular endothelial senescence in a nonhuman primate model. We isolated endothelial cells from left and right femoral arteries in 10 baboons before and after a 7-wk high-fat dietary treatment. We compared the morphological alterations, replicative capacities, and senescence-associated [beta]-galactosidase activities (SA-[beta]-gal) at these two time points. We found that high-fat diet increased the prevalence of endothelial senescence. Endothelial replicative capacities declined dramatically, and SA-[beta]-gal activities increased significantly in postdietary challenge. There was no change in telomeric length using quantitative flow fluorescence in situ hybridization analysis, suggesting that some stressors lead to cell senescence independent of telomere dysfunction. Our findings that high-fat diet causes endothelial damage through the premature senescence suggest a novel mechanism for the diet-induced endothelial dysfunction. senescence-associated [beta]-galactosidase; intercellular adhesion molecule; vascular cell adhesion molecule doi:10.1152/ajpheart.01405.2007

It has been suggested that high-fat (HF) diet exaggerates the stress-induced release of glucocorticoids due to activation of the hypothalamic-pituitary-adrenal (HPA) axis. In an initial experiment, in which rats were fed HF diet for 4 days, we found that HF-fed controls stopped gaining weight, indicating that they were hyperresponsive to the mild stress of tail bleeding but responded the same as low-fat (LF)-fed rats to the more severe stress of restraint. A second experiment confirmed these results when rats fed a HF diet for 4 days showed an exaggerated corticosterone release in response to an intraperitoneal injection of saline and movement to a novel cage, compared with LF-fed rats. Experiment 3 tested the same parameters as experiment 2 but interchanged the diets. This allowed us to differentiate between the effects of the dietary fat and the novelty of the diet. Additionally, this experiment determined whether hyperresponsiveness to mild stress in HF-fed rats was sustained during a prolonged exposure to diet. The results confirmed that a HF diet, not novelty, exaggerated the endocrine stress response after 9 days on the diet but that the effect was no longer present after 23 days on the diet. The hyperresponsiveness of the HPA axis in HF-fed rats is similar to that observed in animals that have been exposed to a significant chronic or acute stress, suggesting that the HF diet may initially be perceived as a stressor. corticotropin-relasing factor; energy intake; hypothalamo-pituitary axis; weight regulation

Insulin resistance in skeletal muscle and heart plays a major role in the development of type 2 diabetes and diabetic heart failure and may be causally associated with altered lipid metabolism. Hormone-sensitive lipase (HSL) is a rate-determining enzyme in the hydrolysis of triglyceride in adipocytes, and HSL-deficient mice have reduced circulating fatty acids and are resistant to diet-induced obesity. To determine the metabolic role of HSL, we examined the changes in tissue-specific insulin action and glucose metabolism in vivo during hyperinsulinemic euglycemic clamps after 3 wk of high-fat or normal chow diet in awake, HSL-deficient (HSL-KO) mice. On normal diet, HSL-KO mice showed a twofold increase in hepatic insulin action but a 40% decrease in insulin-stimulated cardiac glucose uptake compared with wild-type littermates. High-fat feeding caused a similar increase in whole body fat mass in both groups of mice. Insulin-stimulated glucose uptake was reduced by 50-80% in skeletal muscle and heart of wild-type mice after high-fat feeding. In contrast, HSL-KO mice were protected from diet-induced insulin resistance in skeletal muscle and heart, and these effects were associated with reduced intramuscular triglyceride and fatty acyl-CoA levels in the fat-fed HSL-KO mice. Overall, these findings demonstrate the important role of HSL on skeletal muscle, heart, and liver glucose metabolism. glucose metabolism; lipid metabolism; high-fat feeding; insulin action; triglyceride

The effect of consuming meals of different macronutrient content on substrate oxidation following resistance exercise was examined in 9 resistance-trained men (26.2 [+ or -] 2.4 years). Subjects completed 3 resistance exercise bouts of 8 exercises and 1 warm-up set (50% of 10 repetition maximum [RM]), which were followed by 3 sets of 10 repetitions (72.7 [+ or -] 1.9% 10RM), with 60 seconds of rest between sets. Forty-five minutes after exercise, subjects consumed meals of high fat (HF, 37% carbohydrate, 18% protein, and 45% fat), high carbohydrate (HC, 79% carbohydrate, 20% protein, and 1% fat), or water (CON). Fat and carbohydrate oxidation were determined at 15-minute periods after meal consumption for 165 minutes. Blood was collected at preexercise (pre), premeal (0 minutes), and 15, 30, 45, 60, 90, 120, 150, and 180 minutes postmeal and was analyzed for insulin, glucose, triacylglycerols, and glycerol. There were no significant differences among the meal conditions for fat and carbohydrate oxidation. Insulin and glucose concentrations were significantly higher (p < 0.05) following HC at 15, 30, 45, 60, and 90 minutes compared to HF and CON. Triacylglycerol concentrations were significantly higher (p < 0.05) following HF at 90, 120, 150, and 180 minutes compared to HC and CON. Fat and carbohydrate oxidation were not affected by differences in macronutrient meal consumption after an acute bout of resistance training. Different macronutrient consumption does influence insulin, glucose, and triacylglycerol concentrations after resistance exercise. KEY WORDS. substrate oxidation, energy expenditure, excess postexercise oxygen consumption, insulin, glucose, triacylglycerol, glycerol

The ketogenic diet that is used to treat children with severe seizures may increase their risk of developing heart disease by increasing blood cholesterol levels, according to a study of 141 children. A ketogenic diet contains high amounts of fat and low amounts of protein and carbohydrate. This produces substances in the body called ketones.

The aim of this study was examine the effects of high starch (HS) vs. high fat (HF) feeding on blood glycated hemoglobin (GHb[A.sub.1c]) level, thiobarbituric acid-reactive species (TBA-RS) concentration and [delta]-aminolevulinate dehydratase ([delta]-ALA-D) activity in mice. The GHb[A.sub.1c] level was significantly higher in mice fed the HF diet compared with those fed the HS diet. Hepatic, renal, and cerebral TBA-RS concentrations in mice fed the HF diet were significantly greater than in mice fed the HS diet. In addition, positive correlations were found between the GHb[A.sub.1c] and TBA-RS levels for hepatic (P < 0.05; r = 0.46), renal (P < 0.003; r = 0.65), and cerebral (P < 0.001; r = 0.69) tissues. The [delta]-ALA-D hepatic, renal and cerebral activities of mice fed the HF diet were significantly lower than those of mice fed the HS diet. Furthermore, a negative correlation was found between the GHb[A.sub.1c] level and [delta]-ALA-D activity in hepatic (P < 0.001; r = -0.77), renal (P < 0.007; r = -0.60), and cerebral (P < 0.007; r = -0.60) tissues. The results of this study indicate that consumption of a high fat diet promotes oxidative stress related to hyperglycemia, which in turn can stimulate glycation of proteins leading to [delta]-ALA-D inhibition in mice. KEY WORDS: * high fat diet * hyperglycemia * oxidative stress * [delta]-aminolevulinate dehydratase * mice

Previous reports implicate the orexins in eating and body weight regulation. This study investigated possible functional relationships between hypothalamic orexins and circulating hormones or metabolites. In situ hybridization and quantitative PCR were used to examine orexin expression in the perifornical hypothalamus (PF) of rats and mice on diets varying in fat content and with differential propensity toward obesity. The results showed that orexin gene expression was stimulated by a high-fat diet in close association with elevated triglyceride levels, suggesting a functional relationship between these measures. Results obtained in obesity-prone rats and mice revealed a similar increase in orexin in close relation to triglycerides. A direct test of this orexin-triglyceride link was performed with Intralipid, which increased PF orexin expression along with circulating triglycerides. Whereas PF galanin is similarly stimulated by dietary fat, double-labeling immunofluorescence studies showed that orexin and galanin neurons are anatomically distinct. This evidence suggests that the orexins, like galanin, are 'fat-responsive' peptides that respond to circulating lipids. perifornical lateral hypothalamus; triglycerides; high-fat diet; obesity

Bitter melon (BM) is known for its hypoglycemic effect but its effect on rats fed a hyperinsulinemic high fat diet has not been examined. In a dose-response (0.375, 0.75 and 1.5%) study, oral glucose tolerance was improved in rats fed a high fat (HF; 30%) diet supplemented with freeze-dried BM juice at a dose of 0.75% or higher (P < 0.05). At the highest dose, BM-supplemented rats had lower energy efficiency (P < 0.05) and tended (P = 0.10) to have less visceral fat mass. In a subsequent experiment, rats habitually fed a HF diet either continued to consume the diet or were switched to a HF+BM, low fat (LF; 7%) or LF+BM diet for 7 wk. BM was added at 0.75%. Final body weight and visceral fat mass of the two last-mentioned groups were similar to those of rats fed a LF diet for the entire duration. Rats switched to the HF+BM diet gained less weight and had less visceral fat than those fed the HF diet (P < 0.05). The addition of BM did not change apparent fat absorption. BM supplementation to the HF diet improved insulin resistance, lowered serum insulin and leptin but raised serum free fatty acid concentration (P < 0.05). This study reveals for the first time that BM reduces adiposity in rats fed a HF diet. BM appears to have multiple influences on glucose and lipid metabolism that strongly counteract the untoward effects of a high fat diet. J. Nutr. 133: 1088-1093, 2003. KEY WORDS: * bitter melon * glucose tolerance * free fatty acids, * visceral fat * hyperinsulinemia * rats

The prevalence of obesity is increasing. Although the etiology of obesity is complex, dietary factors, particularly the consumption of a high-fat (HF) diet, is considered a risk factor for its development. Nonetheless, a causal role of dietary fat has never been definitively documented, in part because of inadequate animal models. We developed a rat model of diet-induced obesity that will be a powerful tool for assessment of this issue. In four experiments, Long-Evans rats ate ad libitum a synthetic semipurified diet containing 20 g (HF) or 4 g [low-fat (LF)] of fat/100 g of diet or a nonpurified diet. Other rats ate ad libitum the HF diet in amounts matched to the energy intake of the LF rats. When compared over 10 wk of free feeding, HF rats weighed 10% more (P < 0.01) than LF rats and had 50% more body fat (P < 0.01), as well as significant hyperleptinemia and insulin resistance. Compared with rats fed the nonpurified diet, the HF rats had even more marked differences in these variables. The rats fed the HF diet to match the rats fed the LF diet had similar body weights but significantly more adipose tissue than LF rats, suggesting that diet composition and/or energy density of the diet affects fat deposition. This dietary regimen has reproducible effects on body size and composition, and these are similar in male and female rats. This model of diet-induced obesity will be a useful tool for studying the mechanisms by which dietary fat influences the regulation of energy balance. J. Nutr. 133: 1081-1087, 2003. KEY WORDS: * high-fat diet * obesity * insulin * leptin * adiposity * rats

Peroxisome proliferator-activated receptor-[gamma]/ PPAR[gamma]) is the target receptor for thiazolidinedione (TZD) compounds, which are a class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. Paradoxically, however, mice deficient in PPAR[gamma] (PPAR[[gamma].sup.+/-]) are more insulin sensitive than their wild-type (WT) littermates, not less, as would be predicted. To determine whether PPAR[GAMMA] deficiency could prevent the development of the insulin resistance associated with increasing age or high-fat (HF) feeding, insulin sensitivity was assessed in PPAR[[gamma].sup.+/-] and WT mice at 2, 4, and 8 mo of age and in animals fed an HF diet. Because TZDs elicit their effect through PPAR[GAMMA] receptor, we also examined the effect of troglitazone (a TZD) in these mice. Glucose metabolism was assessed by hyperinsulinemic euglycemic clamp and oral glucose tolerance test. Insulin sensitivity declined with age for both groups. However, the decline in the PPAR[[gamma].sup.+/-] animals was substantially less than that of the WT animals, such that, by 8 mo of age, the PPAR[[gamma].sup.+/-] mice were markedly more insulin sensitive than the WT mice. This greater sensitivity in PPAR[[gamma].sup.+/-] mice was lost with TZD treatment. HF feeding led to marked adipocyte hypertrophy and peripheral tissue and hepatic insulin resistance in WT mice but also in PPAR[[gamma].sup.+/-] mice. Treatment of these mice with troglitazone completely prevented the adipocyte hypertrophy and normalized insulin action. In conclusion, PPAR[gamma] deficiency partially protects against age-related insulin resistance but does not protect against HF diet-induced insulin resistance. peroxisome proliferator-activated receptor-[gamma]/deficiency; high-fat diet; aging; insulin resistance; thiazolidinedione; mice

High-fat diets are reported to induce resistance to peripherally administered leptin. In an attempt to develop a model of juvenile diet-induced obesity, mice were weaned onto high-fat diet. Male and female, 35-day-old, C57BL/6J high-fat (45% kcal fat) diet-fed mice housed individually on grid floors did not decrease food intake or body weight in response to intraperitoneal (30 [micro]g), lateral ventricle (5 [micro]g), or third ventricle (0.5 [micro]g) injections of leptin. Body weight and fat were significantly reduced by 13-day intraperitoneal infusions of 10 [micro]g leptin/day, which doubled circulating leptin. Leptin infusion also reduced body fat in weanling, high-fat diet-fed NIH Swiss mice. Group housing mice on bedding prevented loss of fat in high-fat diet-fed male and female NIH Swiss and female C57BL/6J mice. These results indicate that peripherally infused leptin reduces fat in part by increasing thermogenesis and that inhibition of food intake in high-fat diet-fed mice requires either chronic activation of central leptin receptors or is independent of receptors that inhibit feeding in response to an acute central injection of leptin. food intake; body weight; body composition; serum leptin

We compared the effects of a high fat diet [38.4% of energy (E%) from fat; HSAFA diet, polyunsaturated/saturated fatty acid (P/S) ratio = 0.14], a low fat diet (19.7 E% from fat; LSAFA diet, P/S = 0.17), both based on coconut oil, and a diet with a high content of mono- and polyunsaturated fatty acids (PUFA; 38.2 E% from fat; HUFA diet, P/S = 1.9) on serum lipoproteins. The 25 women studied consumed each diet for 3-wk periods in a crossover design. The two high fat diets were identical except for the quality of the test fat. The LSAFA diet was identical to the HSAFA diet except that half the fat was replaced by carbohydrates. Serum total cholesterol, LDL cholesterol and apoB concentrations did not differ between the HSAFA and the LSAFA diet periods. Total cholesterol, LDL cholesterol and apoB were lower when women consumed the HUFA diet than when they consumed the other two diets. HDL cholesterol and apoA-I were 15 and 11%, respectively, higher when women consumed the HSAFA diet than when they consumed the LSAFA diet; HDL cholesterol and apoA-I were lower when women consumed the HUFA diet than when they consumed the HSAFA diet, but not the LSAFA diet. The LDL cholesterol/HDL cholesterol and apoB/apoA-I ratios were higher when women consumed the LSAFA diet than when they consumed the HSAFA diet. The LDL/HDL cholesterol ratio was higher when women consumed either the LSAFA or the HSAFA diet than when they consumed the HUFA diet, whereas apoB/apoA-I was higher when women consumed the LSAFA diet than when they consumed the HUFA diet. Triacylglycerol and VLDL cholesterol were higher when women consumed the LSAFA diet than when they consumed either the HSAFA or the HUFA diet. We conclude that, to influence the LDL/HDL cholesterol ratio, changing the proportions of dietary fatty acids may be more important than restricting the percentage of total or saturated fat energy, at least when derived mainly from lauric and myristic acids, both of which increase HDL cholesterol. KEY WORDS: * apolipoprotein A-I * apolipoprotein B * coconut oil * lauric acid * myristic acid

Studies suggest that heated oils contribute to the presence of oxidized components in the circulating lipoproteins and to the development of atherosclerosis in animals. We evaluated the effects of 11-13 wk of consumption of a well defined dietary oxidized fatty acid, 13-hydroxylinoleic acid (13-HODE) (8 mg), on atherosclerotic lesion development and plasma cholesterol concentrations in mice fed diets varying in fat and cholesterol contents. LDL receptor knockout mice were used in two feeding studies. In study 1, oxidized fatty acid consumption in association with a high fat diet increased aortic lesion areas by > 100% (P < 0.05). Surprisingly, oxidized fatty acid intake also tended to increase plasma total cholesterol (P = 0.12) and LDL cholesterol (P < 0.05) as well as oxidative stress as measured by higher levels of autoantibodies to oxidatively modified proteins (P = 0.008). However, in mice fed a nonpurified diet, oxidized fatty acids were not atherogenic and may even have been beneficial, as indicated by a lower plasma triglyceride (TG) concentration (P < 0.05). In study 2, mice were fed either a high fat, medium fat or low fat diet to evaluate whether the increase in aortic lesions due to oxidized fatty acid consumption in study 1 was a result of the associated higher plasma total and LDL cholesterol concentrations. In study 2, 13-HODE-treated mice in the medium and low fat diet groups but not those fed the high fat diet had larger atherosclerotic lesions (P < 0.05). Additionally, plasma total and LDL cholesterol as well as TG were not affected by HODE treatment. However, the total cholesterol:HDL cholesterol ratio was higher in treated mice (P < 0.05) and HDL cholesterol was lower in HODE-treated mice that were fed the low fat diet (P < 0.05). Our results suggest that, in mice fed cholesterol, oxidized fatty acids may be atherogenic, both in terms of increased oxidative stress (as seen in study 1) and by increasing the atherogenicity of the plasma cholesterol profile. KEY WORDS: * lipid hydroxide * atherosclerotic lesions * plasma cholesterol * oxidized lipoproteins * autoantibodies

This study evaluated the relative contribution of insulin-dependent mechanisms vs. mechanisms independent on dynamic insulin for glucose intolerance induced by high-fat diet. C57BL/6J mice underwent a frequently sampled intravenous glucose tolerance test (1 g/kg glucose) at I wk and 1, 3, and 10 mo after initiation of a high-fat diet (58% fat; control diet 11% fat) to measure glucose effectiveness ([S.sub.G]) and disposition index (DI), i.e., insulin sensitivity ([S.sub.I]) times early or total insulin secretion. Glucose disappearance ([K.sub.G]) and [S.sub.I] were reduced in high-fat-fed mice at all time points. Total (50 min) insulin secretion was sufficiently increased at all time points to compensate for the reduced [S.sub.I], as judged by normal [DI.sub.50 min]. In contrast, early (10 min) insulin secretion was not sufficiently increased; [DI.sub.10 min] was reduced after 1, 3, and 10 mo. [S.sub.G] was reduced after 1 wk; the reduction persisted throughout the study period. Thus glucose intolerance induced by high-fat diet is, in early phases, solely explained by reduced glucose effectiveness, whereas insufficient early insulin secretion is of importance after long-term feeding. glucose tolerance; glucose intolerance; insulin secretion; high-fat diet

Ketogenic diets have been used to treat seizure disorders of children and recently it was shown to increase the drug-induced seizure threshold in rats. Protein phosphorylation is a major regulatory mechanism of signal transduction that has been implicated in modulating neuronal excitability. We investigated the basal protein phosphorylation in microslices from different brain regions (hippocampus, cerebral cortex and cerebellum) of young rats fed a ketogenic diet, and we evaluated the effect of this diet on weight development and health of these rats based on serum biochemistry. Thirty-day-old rats consumed ad libitum ketogenic (high fat) or control diets for 8 wk. Rats consuming the high fat diet had ketonemia without signs of undernutrition or illness. Microslices were incubated in media containing [sup.32]P-phosphate, and [sup.32]P-phosphoprotein content was analyzed by one- or two-dimensional electrophoresis followed by autoradiography. Basal protein phosphorylation was greater in brain slices from ketogenic rats. Different increments of synapsin I, GAP-43 and GFAP phosphorylation were observed in two-dimensional autoradiography. A ketogenic diet induced metabolic changes affecting the basal status of protein phosphorylation. This change could affect the mechanisms of signal transduction in neural cells involved in the increase in the seizure threshold. KEY WORDS: * ketogenic diet * protein phosphorylation * [beta]-hydroxybutyrate * epilepsy * rats