Obesity is a chronic metabolic disorder caused by imbalance between energy intake and expenditure, and is one of the principal causative factors in the development of metabolic syndrome, diabetes and cancer. COH-SR4 (‘‘SR4’’) is a novel investigational compound that has anti-cancer and anti-adipogenic properties. In this study, the effects of SR4 on metabolic alterations inhighfatdiet (HFD)-inducedobese C57BL/J6 mice were investigated. Oral feeding of SR4 (5 mg/kg bodyweight.) in HFD mice for 6 weeks significantly reduced bodyweight, prevented hyperlipidemia and improved glycemiccontrol without affecting food intake. These changes were associated with marked decreases in epididymal fat mass, adipocyte hypertrophy, increased plasma adiponectin and reduced leptin levels. SR4 treatment also decreased liver triglycerides, prevented hepaticsteatosis, and normalized liver enzymes. Western blots demonstrated increased AMPK activation in liver and adipose tissues of SR4-treated HFD obesemice, while gene analyses by real time PCR showed COH- SR4 significantly suppressed the mRNA expression of lipogenic genes such as sterol regulatory element binding protein-1c (Srebf1), acetyl-Coenzyme A carboxylase (Acaca), peroxisome proliferator-activated receptor gamma (Pparg), fatty acid synthase (Fasn), stearoyl-Coenzyme A desaturase 1 (Scd1), carnitine palmitoyltransferase 1a (Cpt1a) and 3-hydroxy-3-methyl- glutaryl-CoA reductase (Hmgcr), as well as gluconeogenic genes phosphoenolpyruvate carboxykinase 1 (Pck1) and glucose- 6-phosphatase (G6pc) in the liver of obesemice. In vitro, SR4 activates AMPK independent of upstream kinases liver kinase B1 (LKB1) and Ca2+/calmodulin-dependent protein kinase kinase b (CaMKKb). Together, these data suggest that SR4, a novel AMPK activator, may be a promising therapeutic compound for treatment of obesity, fatty liver disease, and related metabolic disorders.
It has been suggested that angiogenesis modulates adipogenesis and obesity. This study was undertaken to determine whether ALS-L1023 (ALS) prepared by a two-step organic solvent fractionation from Melissa leaves, which exhibits antiangiogenic activity, can regu- late adipose tissue growth. The effects of ALS on angiogenesis and extracellular matrix remodeling were measured using in vitro assays. The effects of ALS on adipose tissue growth were investigated inhighfatdiet-inducedobesemice. ALS inhibited VEGF- and bFGF-induced endothelial cell proliferation and suppressed matrix metalloproteinase (MMP) activity in vitro. Compared to obesecontrolmice, administration of ALS to obesemice reduced bodyweight gain, adipose tissue mass and adipocyte size without affecting appetite. ALS treatment decreased blood vessel density and MMP activity in adipose tis- sues. ALS reduced the mRNA levels of angiogenic factors (VEGF-A and FGF-2) and MMPs (MMP-2 and MMP-9), whereas ALS increased the mRNA levels of angiogenic inhibitors (TSP-1, TIMP-1, and TIMP-2) in adipose tissues. The protein levels of VEGF, MMP-2 and MMP-9 were also decreased by ALS in adipose tissue. Metabolic changes in plasma lipids, liver triglycerides, andhepatic expression of fatty acid oxidation genes occurred during ALS-inducedweight loss. These results suggest that ALS, which has antiangiogenic and MMP inhibitory activities, reduces adipose tissue mass in nutritionally obesemice, demon- strating that adipose tissue growth can be regulated by angiogenesis inhibitors.
To determine whether TSP1 deficiency affects the development of obesity, male TSP1-/- miceand wild type controls were fed with a low fat (LF, 10% fat) or highfat (HF, 60% fat) diet for 16 weeks. The bodyweight was measured weekly. Prior to the end of the study, body composition was analyzed using EchoMRI. The results showed that bodyweightandfat mass were similar between the TSP1-/- and wild type controlmice under LF or HF feeding conditions (Figure 1). In addition, highfat feeding significantly increased plasma triglyceride levels in WT and TSP1-/- mice. However, plasma triglyceride levels were less in HF-fed TSP1-/- mice than those in HF-fed WT mice (Table 2). Total cholesterol levels were similarly increased in both HF-fed WT and TSP1-/- mice (Table 2). We also measured metabolic parameters such as food intake, oxygen consumption and physical activity, and did not observe a difference between HF-fed WT miceand HF-fed TSP1-/- mice (data not shown). Together, these data suggest that TSP1 deficiency does not affect the development of obesity.
Metabolic syndrome, diabetes and diabetes complications pose a growing medical challenge worldwide, accentuating the need of safe and effective strategies for their clinical management. Here we present preclinical evidence that the sorbitol derivative meglumine (N-methyl-D-glucamine) can safely protect against several features of metabolic syndrome and diabetes, as well as elicit enhancement in muscle stamina. Meglumine is a compound routinely used as an approved excipient to improve drug absorption that has not been ascribed any direct biological effects in vivo. Normal mice (SV129) administered 18 mM meglumine orally for six weeks did not display any gastrointestinal or other observable adverse effects, but had a marked effect on enhancing muscle stamina and at longer times in limiting weight gain. In the established KK.Cg- Ay/J model of non-insulin dependent diabetes, oral administration of meglumine significantly improved glycemiccontroland significantly lowered levels of plasma and liver triglycerides. Compared to untreated control animals, meglumine reduced apparent diabetic nephropathy. Sorbitol can improve blood glucose uptake by liver and muscle in a manner associated with upregulation of the AMPK-related enzyme SNARK, but with undesirable gastrointestinal side effects not seen with meglumine. In murine myoblasts, we found that meglumine increased steady-state SNARK levels in a dose- dependent manner more potently than sorbitol. Taken together, these findings provide support for the clinical evaluation of meglumine as a low-cost, safe supplement offering the potential to improve muscle function, limit metabolic syndrome and reduce diabetic complications.
mal models [20,21]. Several transcription factors involved in cholesterol metabolism are suggested as regulatory factor for NPC1L1 expression. SREBP2, a transcription factor for choles- terol biosynthesis shows positive relationship with mRNA ex- pression of NPC1L1 in human hepatoma HepG2 cells andin- testinal Caco2 cells [22-24]. SREBP2 together with hepatocyte nuclear factor 4α synergistically activates human NPC1L1 promoter . In vivo andin vitro studies demonstrate the regulatory efects of nuclear receptors including liver X recep- tor (LXR), retinoid X receptor, and peroxisome proliferator- activated receptors (PPARs) on NPC1L1 transcription. PPARα agonist, fenofibrate administered mice remarkably decrease intestinal cholesterol absorption accompanied with the reduc- tion in NPC1L1 mRNA expression . PPARδ agonist also decreases mRNA level of NPC1L1 in small intestine andin- creases fecal sterol excretion. A single dose of LXR agonist miceand treatment of LXR activators, GW3965 and T0901317 in the human enterocyte cell line reduce mRNA expression of NPC1L1 . However, the effects of nuclear receptors on NPC1L1 transcription are discrepant according to tissue and species.
Our results do not agree with the recent study by Lee et al.  in which rottlerin and a PKCd short peptide inhibitor blocked fibrogenic gene expression and fibrosis inmice fed a MCD diet for 3 weeks and treated with LPS for 6 h. However, the LPS treatment lead to significant increases (from 8- to 15-fold) inhepatic TGF-b, a-SMA, and pro-collagen-1 a1 mRNA expression compared to that observed in the untreated, MCD diet fed mice. Further, Masson’s trichrome staining was observed in the 6 h LPS treated, MCD diet fed mice but not in the untreated, MCD diet fed mice. Thus, fibrosis development appears to be an acute response in the LPS-treated, MCD fed mice compared to fibrosis development in the present study which was observed inmice fed the MCD diet for 8 weeks. Finally, the LPS independent effects of PKCd on key pathophysiological features of NASH are not known in the LPS-treated, MCD diet model of NASH. Further, given that there are key pathophysiological features in human patients with NASH (obesity and whole body insulin resistance) which are not present in the MCD diet model of NASH, it is possible that PKCd deletion in the context of obesity and whole body insulin resistance may reduce fibrosis.
of lipid accumulation by PCN may also contribute indirectly in maintenance of glucose homeostasis because lipotoxicity in the liver and pancreas exerts an important function in type-2 diabetes . It is still unknown, however, how PCN improves obesity-induced insulin resistance. Decrease infat accumulation in WAT may benefit improved insulin sensitivity. It’s well known that adipocytes in WAT release significant amounts of pro-inflammatory cytokines such as TNFa, IL-6 and IL-1. Obesity also resulted in more macrophage infiltration in adipose tissue . These pro-inflammatory cytokines and chronic inflammation infat are major factors in causing the whole- body obesity-related insulin resistance . Our unpublished data show that PCN decreases macrophage accumulation and pro-inflammatory cytokine release in adipose tissue. In addition, the NFkB pathway plays a crucial role in production of pro- inflammatory cytokines. While activation of PXR inhibits the Figure 5. Effect of PCN treatment on expression of genes involved in lipogenesis and lipids uptake. Four h after treatment, mice were sacrificed and livers were harvested. The expression of genes involved in the cholesterol metabolism (A, B), lipids metabolism (C) and lipids uptake (D) were measured by real-time PCR. Each data point represents the average 6 SD of 4 animals in each group. #P,0.05, ##P,0.01 compared to chow-DMSO group; *P,0.05, **P,0.01 compared to high-fatdiet-DMSO group. Abbreviations: Cyp7a1, cholesterol 7 alpha-hydroxylase gene; HMGCR, 3-hydroxy-3-methylglutaryl coenzyme A reductase gene; Cyp27a1, sterol 27-hydroxylase; Abca1, Abcg1, ATP-binding cassette transporter A1 and G1; SREBP-1c, sterol regulatory element-binding protein 1c; FAS, fatty acid synthase; Scd-1, stearoyl CoA desaturase 1; and L-FABP, liver fatty- acid-binding protein.
of Minnesota specific pathogen-free animal facility, where light and temperature were regulated. TCF8 null mice were generated by Dr. Yujiro Higashi and colleagues (Osaka University, Osaka, Japan) by b–galactosidase (b-gal) insertion into Exon 1 as described previously [15,25], and heterozygous (TCF8+/2) males were provided by Dr. Jennifer Richer, University of Colorado, Aurora, CO. The colony was generated and maintained on a C57BL/6 background. Female breeder mice were purchased from Charles River Biological Laboratories (Wilmington, MA). Geno- mic DNA was isolated from ear snips, and polymerase chain reactions (PCR) were performed to determine genotype. To generate products, Choice-Taq (#CB4050-2 Denville Scientific, Metuchen, NJ) with its accompanying 10X buffer and 25 mM dNTPs were used. PCR reactions were done for 35 cycles consisting of 95uC for 30 sec, 61uC for 30 sec, and 72uC for 1 min. Products were amplified using the allele-specific primers designed by Jennifer Richer (University of Colorado) listed below. The TCF8 forward and reverse primers were used to detect wild type (WT) animals (193 bp product), and the TCF8 forward and b- gal reverse primers were used to detect heterozygous animals (537 bp product).
The esterification and maturation processes of VLDL are associated with ADRP. The level of TG in the cytosol is reduced in ADRP-deficient mice, whereas TG concomitantly accumu- lates in the microsome . The microsomal pool is coupled to VLDL secretion, whereas the cytosolic pool is not [44, 45]. ADRP is suggested to negatively regulate the esterification of VLDL and TG output, and the overexpression of ADRP leads to lipid accumulation in the liver. Previous research showed that ADRP expression is higher in NAFLD than normal livers . The absence of ADRP reduces the amount of TG in the liver and protects the liver against diet-induced fatty liver development . In our study, octreotide treatment reversed the up- regulation of ADRP inhigh-fatdiet-inducedobese rats. The down-regulation of ADRP in the octreotide-treated group may positively regulate hepatic microsomal TG accumulation and promote esterification and the secretion of TG-rich VLDL to ultimately reduce the abnormal accumulation of hepatic TG.
transcript levels for all the tested genes between these two groups. The animals sacrificed 10 days after the surgery provided evidences for the feedback consequence of lipectomy. The liver of these animals possessed higher mRNA levels of lipogenic (ACC1, FAS), sterol synthetic (HMG) and gluconeogenic (FBP1, G6Pase) enzymes than the sham-operated ones, suggesting that lipectomy stimulated the hepatic anabolic pathways with an intention to restore the loss of energy storage. Excess weight gain and lipid accumulation could also be a result of energy conservation. However, the genes involved in b-oxidation of fatty acid, and energy expenditure were not affected by lipectomy. Furthermore, AMPK which is known to activate fatty acid oxidation and glycolysis, and to inhibit fatty acid, TG, cholesterol and glycogen synthesis and gluconeogenesis  was also unaffected. A surprising result is that the expression of HSL was induced by fat removal, while de novo synthesis of fatty acid was enhanced at the same time. We speculate that these might lead to excess accumulation of free fatty acids that has been shown to cause lipotoxicity and inflammation of the liver . Taken
Our findings of decreased lymph node size and architecture are also supported by recent work reported by Thomas et al using K14-VEGF-R3-Ig mice . These mice express a soluble VEGF-R3 antibody in the skin and, as a result, have severely hypoplastic dermal lymphatic vessels and decreased lymphatic transport. Similar to our study, Thomas et al reported markedly decreased lymph node size and abnormal architecture (B cells scattered among T cells rather than arranged in a follicular pattern) and suggested that lymphatic fluid flow to the lymph node has important regulatory effects on lymph node homeostasis. In addition, similar to our study, the authors reported that the expression patterns of CCL21 was abnormal in K14-VEGF-R3-Ig mice. Taken together, our findings and those of Thomas et al support the hypothesis that lymphatic flow to the lymph node is a critical regulator of lymph node architecture and morphology. This hypothesis is further supported by previous studies demon- strating that the expression of CCL21 by lymph node reticular cells is regulated by fluid shear and lymph node interstitial flow . It is likely, however, that multiple mechanisms regulate CCL21 expression in these circumstances since it is known that impaired steady state dendritic cell migration to lymph nodes also results in abnormal T/B cell distribution by regulating T zone fibroblastic reticular cell expression of CCL21 and VEGF . Figure 6. Obesity causes changes in the architecture and cellular composition of lymph nodes. A. Representative florescent micrograph (2.56 magnification) of inguinal lymph nodes harvested from controlandobesemiceand stained for B cells (B220; purple) and T cells (CD3; green). Note loss of follicular pattern and disorganization inobesemice. B. Representative florescent micrographs (2.5x) of inguinal lymph nodes harvested from control (left panels) andobese (right panels) wild-type mice stained for CCL21 (red) and DAPI (blue). CCL21 expression is shown on top panels with DAPI overlay on the bottom. Dotted circled represent follicular regions. Note loss of CCL21 expression gradients inobese animals. C. Representative whole mount immunofluorescent staining (Green = LYVE-1; Red = CCL21; Blue = DAPI) of ear sections from control (top) andobese (bottom). Sections are shown at 636 magnification. LYVE-1 staining is shown on the left; CCL21 is the middle panel; overlay is shown on the right panels. Dashed lines in the middle panel is the region of LYVE-1 vessel. D. Mean area of LYVE-1/CCL21 co-localization (presented as a percentage of LYVE-1 area overall) incontrolandobesemice. E., F. G., H. Flow cytometry analysis of T-helper cells (CD45+/CD3+/CD4+; E), cytotoxic T cells (CD45 + /
The daily dose of infliximab (0.5 mg/kg) and schedule of administration (9:00 a.m. and 5:00 p.m.) were based on a previous study (Araújo et al. 2007). The treatment with infliximab or saline started on the first day of the introduction of the HFD and was maintained until the day before the experiments when the animals were food deprived from 5:00 p.m. All the experiments were performed in 15 h fasted mice (5:00 p.m. – 8:00 a.m.) when the mice were anesthetized with ip thiopental (120 mg/kg). After laparotomy, blood was collected from the cava vein for glucose determination (Bergmeyer and Bernt 1974) and the liver perfusion was started immediately. The in situ liver perfusion technique was done as previously described (Galende et al. 2009; Oliveira-Yamashita et al. 2009). Figure 1 showed a demonstrative experiment in which after a pre- infusion period (10 min), L-alanine was infused during 60 min, followed by a post-infusion period (10 min without L-alanine) to allow the return of basal glucose production values of the pre-infusion period. The samples of the effluent perfusion fluid were collected each 5 min and the glucose concentration was measured. The difference between the glucose production during and before L-alanine infusion represented the glucose production from gluconeogenesis. The areas under the curves (AUC) of the infusion period with L- alanine were expressed as µmol/g. In addition to glucose (Bergmeyer and Bernt 1974), the production of pyruvate (Czok and Lamprecht 1974), urea (Gutmann and Bergmeyer 1974) and L-lactate (Gutmann and Wahlefeld 1974) in the liver were also evaluated. At the end of the experiment, the liver was removed and weighed to allow precise metabolic calculations and the correction of flow rates.
We previously showed that obesity-induced early diabetes has a detrimental impact on reti- nal light sensitivity and health . Mice under chronic high-fat-diet (HFD) not only become obese, they also develop a stable hyperglycemia with a progressively increased hyperinsuline- mia over time, indicating the progressive worsening of insulin resistance . These obesemice frequently develop chronic inflammation within adipose tissues [36–38], which is a sig- nificant factor contributing to systemic insulin resistance [38–42] and hyperglycemia , two hallmarks of type 2 diabetes. Unlike other diabetic mouse models derived from monogenic dis- orders or chemical destruction of β-cells, the HFD-induced diabetic mouse model is widely used in studies on pathophysiology of obesity and type 2 diabetes, such as mechanisms of impaired glucose tolerance and insulin resistance, as well as other diabetic complications [35,43], and it is more clinically relevant to obesity-associated type 2 diabetes in humans [35,43]. These HFD-induced diabetic mice also have structural and functional deficits in the retina similar to certain characteristics found in other DR animal models, including defects in the inner retinal light responses, lesions in the retinal vasculature, and thickness of Bruch's membrane . Furthermore, mice fed with a HFD containing 42% fat calories for 12 months have significantly greater numbers of atrophic capillaries and pericyte ghosts compared to mice fed with a normal diet . Because HFD-induced DR inmice is characterized by its
compared with untreated mice), and increased hepcidin gene expression. HDAC inhibition inin vivo models of physiologic and pathologic hepcidin suppression showed a consistent effect in raising hepcidin levels. Treatment of thalassemic mice with low-dose PB increased hepcidin levels and reduced serum iron concentrations, indicating a physiologic effect on cellular iron export. Hepcidin was also raised by PB in Hfe−/− mice. However, PB elevated liver iron in the Th3/+ and Hfe−/− animals, limiting its clinical value. PB also increased serum iron in the Hfe−/− model. Similar effects were seen with the HDAC3 inhibitor RGFP966 in iron-deﬁcient mice. While the explanation for increased liver iron is unclear, it may potentially be due to suppressed erythropoiesis and therefore reduced iron uptake by the marrow for heme synthesis. However, PB did not change erythroid maturation and only slightly reduced bone marrow erythroferrone expression inmice treated with Epo. Likewise, PB and RGFP966 did not appear to affect BMP signaling given BMP target gene expression was unchanged. Thus, effects of HDAC inhibition on hepcidin elevation appear direct, and physiologic, with reductions in ferroportin and increased spleen iron, while elevations in liver iron remain difﬁcult to explain and limit potential clinical application at this stage.
ABSTRACT: Ilex paraguariensis A. St.-Hil., Aquifoliaceae, is a species native to the subtropical and temperate regions of South America, used in beverages prepared by infusion such as teas, chimarrão and tererê. To investigate the physiological effects of I. paraguariensis on the metabolism of fats and sugars in Wistar rats, following the ingestion of erva-mate tea, four experimental groups were constructed: Lipid Control Group (receiving water andhigh-fatdiet); Lipid Tea Group (extract of I. paraguariensis andhigh-fatdiet); the Sugar Control Group (water andhigh-sugar diet); and Sugar Tea Group (extract of I. paraguariensis andhigh-sugar diet). The animals received their particular diet for 60 days, and were weighed weekly. After this period, the plasma concentrations of cholesterol, glucose and triacylglycerides were determined, together with the weight of visceral fat. The data were subjected to statistical analysis with a significance level of p<0.05. The results show that the ingestion of erva-mate affected bodyweight, visceral fatand plasma glucose, cholesterol and triacylglyceride levels.
deposition , and a low level of circulating adiponectin is closely associated with type2 diabetes . We therefore analyzed the effect of expression changes of the paternal imprinted genes, Peg3 and Igf2, inin vitro studies using differentiated 3T3-L1 cells. We demonstrated that Igf2 effectively inhibited TNF-a-induced increase of MCP-1 expression in 3T3-L1 adipocytes and up- regulated Glut4 and adiponectin transcription. In addition, we also showed that Igf2 increased the insulin-stimulated glucose uptake in 3T3-L1 adipocytes together with a low-dose TNF-a treatment. These results suggest that Igf2 has an anti-inflammatory effect and enhances glucose metabolism. However, we did not detect an effect of Peg3 down-regulation or up-regulation on the expression of MCP-1, Glut4, or adiponectin. Further studies are needed to understand the effect of Peg3 on chronic low-grade inflammation. The glucose tolerances of B6 and PWK mice fed a controldiet drastically differed. In B6 mice, a HFD is associated with glucose tolerance due to changes in insulin sensitivity and insulin secretion [29,30,31,32]. The difference in glucose clearance between B6 and PWK mice might be due to a difference in insulin secretion or insulin sensitivity. One possible factor is the serum adipokine concentration. Adipose tissue produces and secretes adipokines such as adiponectin , and adiponectin has insulin-sensitizing and glucose-clearing effects [34,35]. A high serum concentration of adiponectin might contribute to the enhanced glucose clearance
A high-fatdiet consumption has been associated with several disease states including obesity and inflammatory bowel disease. The main hypothesis of this body of work is that different fatty acids will result in different effects on these states: a high-saturated fat (SAT) diet would have deleterious effects, while a high-polyunsaturated fatdiet (PUFA) would have beneficial effects. The present thesis is divided into two studies. The aim of the first study was to investigate the effects of visceral (epididymal) lipectomy (surgical adipose tissue removal) in rats submitted to different high-fat diets. The rats were allocated into three groups; a high-saturated fatdiet (SAT), a high-polyunsaturated fatdiet (PUFA) and a controldiet (CON). Following eight weeks, rats in each group were allocated to lipectomy (L) or a sham operation (S); animals were euthanized three weeks after surgery. Glucose and insulin tolerance tests, lipid profile and adiposity were measured prior to and three weeks following surgery. Cytokines and insulin levels were measured only at the end of the experiment. We showed that when L was performed following a SAT diet there was a compensatory growth of the retroperitoneal fat depot and increased TNF-α levels which resulted in decreased insulin sensitivity, increased cholesterol levels and an increased fatty liver. However, when L was performed following a PUFA diet these deleterious effects were not shown likely due to increased brown adipose depot and an improved inflammatory response compared to the SAT diet. The second study aimed to evaluate the effects of the SAT and PUFA diets inmice with ulcerative colitis induced by DSS (dextran sodium sulfate). The disease was induced during a five day period, after which the mice recovered for a further five days
Despite the large volume of published studies using experimental models of MS, it is still challenging to find a model that most closely approximates human MS. Ex- perimental models of diet-induced MS vary widely in the induction of MS disturbances [15-18], mainly due to the wide variation in the proportion and/or the types of nu- trients that compose the diets and/or the different ages of the animals used. This wide variability of the proto- cols used in studies on MS limits the reproducibility of the dietary treatments used and comparisons of pub- lished data, making clear the need for a precise defin- ition of the nutritional intervention to induce in animal models, the disturbances typical of human MS. In addition, is not yet fully established the effect of different diets of MS in lipid metabolism and ectopic fat depos- ition in rats of different ages.
Introduction/Aim: The gut has shown to have a pivotal role on the pathophysiology of metabolic disease. Food stimulation of distal intestinal segments promotes enterohormones secretion influencing insulin metabolism. In diabetic rats, oral insulin has potential to change intestinal epithelium behavior. This macromolecule promotes positive effects on laboratorial metabolic parameters and decreases diabetic intestinal hypertrophy. This study aims to test if oral insulin can influence metabolic parameters and intestinal weightinobese non-diabetic rats. Methods: Twelve weeks old Wistar rats were divided in 3 groups: control (CTRL) standard chow group; highfatdiet low carbohydrates group (HFD) and HFD plus daily oral 20U insulin gavage (HFD+INS). Weightand food consumption were weekly obtained. After eight weeks, fasting blood samples were collected for laboratorial analysis. After euthanasia gut samples were isolated. Results: Rat oral insulin treatment decreased bodyweight gain (p<0,001), fasting glucose and triglycerides serum levels (p<0,05) an increased intestinal weight of distal ileum (P<0,05). Animal submitted to highfatdiet presented higher levels of HOMA-IR although significant difference to CT was not achieved. HOMA-beta were significantly higher (p<0.05) in HFD+INS. Visceral fat was 10% lower in HFD+INS but the difference was not significant. Conclusions: In non-diabetic obese rats, oral insulin improves metabolic malfunction associated to rescue of beta-cell activity.