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Vonoprazan is a potassium competitive acid blocker used to treat erosive gastroesophageal reflux disease (GERD) with stronger, more stable acid-suppressing effects than proton pump inhibitors (PPIs). This study clarified the usefulness and superiority of vonoprazan administered every second day over PPIs in the maintenance therapy of erosive GERD.This is a prospective, multicenter, open-label, two-period randomized cross-over study. Patients were randomized to either the vonoprazan-lansoprazole (VP-LZ) group, who were given vonoprazan 10 mg for the first 4 weeks and then lansoprazole 15 mg for the next 4 weeks both administered once every second day, or the lansoprazole-vonoprazan (LZ-VP) group, who were treated in reverse. GERD symptoms were compared using symptom diaries, the frequency scale for symptoms of GERD (FSSG), and the gastrointestinal symptom rating scale (GSRS).We enrolled 122 patients between December 2017 and May 2019. Symptoms were well controlled in vonoprazan administration and lansoprazole administration were 93.6% and 82.1%, respectively, with a significant difference on McNemar's test (P = 0.003). During the second 4 weeks, 94.4% and 76.7% of patients in the VP-LZ and LZ-VP groups, respectively, were well controlled following for ≥ 6 consecutive days a week (P = 0.009). During the first 4 weeks, 96.7% and 80.0% of patients were well controlled with 1 weekly in the VP-LZ and LZ-VP groups, respectively, during the first 4 weeks (P = 0.007). GERD symptoms, assessed via FSSG and GSRS, significantly decreased with vonoprazan administration once every second day.Vonoprazan administered once every second day could be an effective alternative to PPIs in the maintenance treatment of erosive GERD (UMIN000030393).

Aims/Introduction To explore the relationships between periodontitis and microvascular complications as well as glycemic control in type 2 diabetes patients. Materials and Methods This multicenter, hospital-based, cross-sectional study included 620 patients with type 2 diabetes. We compared the prevalence and severity of periodontitis between patients with ≥1 microvascular complication and those without microvascular complications. We also compared the prevalence and severity of periodontitis among patients with different degrees of glycemic control. Results After adjusting for confounding factors, multiple logistic regression analysis showed that the severity of periodontitis was significantly associated with the number of microvascular complications (odds ratio 1.3, 95% confidence interval 1.1–1.6), glycated hemoglobin ≥8.0% (64 mmol/mol; odds ratio 1.6; 95% confidence interval 1.1–2.3), and older age (≥50 years; odds ratio 1.7; 95% confidence interval 1.1–2.6). However, the prevalence of periodontitis was not significantly associated with the number of microvascular complications, but was associated with male sex, high glycated hemoglobin (≥8.0% [64 mmol/mol]), older age (≥40 years), longer duration of diabetes (≥15 years) and fewer teeth (≤25). Furthermore, propensity score matching for age, sex, diabetes duration and glycated hemoglobin showed that the incidence of severe periodontitis was significantly higher among patients with microvascular complications than among those without microvascular complications (P < 0.05). Conclusions The number of microvascular complications is a risk factor for more severe periodontitis in patients with type 2 diabetes, whereas poor glycemic control is a risk factor for increased prevalence and severity of periodontitis.

New erythropoiesis-stimulating agents with a longer half-life have been developed for the treatment of anemia in patients with end-stage renal disease. This study evaluated the efficacy of darbepoetin alfa (DA) and long-acting epoetin beta pegol (continuous erythropoietin receptor activator, CERA) in patients on peritoneal dialysis (PD). Twenty-nine patients who had undergone PD for at least 6 months and were iron replacement-naive and negative for inflammatory parameters were enrolled. Hemoglobin (Hgb) levels and blood pressure were evaluated before and after switching from DA to CERA. Percent transferrin saturation (TSAT), serum ferritin levels and blood pressure were also assessed. Twenty-eight patients were subject to the analysis, excluding one patient with a decrease in Hgb by ≥10%. Switching from DA to CERA did not alter Hgb levels. The doses of DA and CERA after 12 month treatment of each agent were 118.48 ± 79.63 and 89.88 ± 47.50 μg/4 weeks, respectively (conversion ratio, 1:0.76). The CERA dose administered during the final 6 months was abated, compared with that given during the initial 6 months (P = 0.035). The frequency of CERA injection over a 12-month period was less than that of DA (10.0 ± 3.0 vs. 16.4 ± 5.0, P

A 60-year-old male presented to our hospital for further investigation of abnormal findings on an upper gastrointestinal series. Esophagogastroduodenoscopy demonstrated atrophic gastritis and a submucosal tumor (SMT) at the anterior wall of the antrum. The patient was positive for serum anti-Helicobacter pylori (H. pylori) antibody and H. pylori eradication therapy was performed. Five months later, the SMT showed a remarkable morphological change in that an ulcer had developed on its apex, and partial gastrectomy was performed. Pathological examination suggested an inflammatory fibroid polyp (IFP), and genetic analysis revealed no mutation in the platelet-derived growth factor receptor alpha gene. This case suggests that H. pylori infection plays an important role in the etiology of IFPs.

Lymphoproliferative disorders (LPDs) occur more frequently in rheumatoid arthritis (RA) patients treated with immunosuppressive agents than in the non-RA population. However, the various forms of disease progression have not yet been elucidated in detail. We encountered a case of Epstein-Barr virus (EBV)-positive atypical polymorphous LPD in the cervical and intraabdominal lymph nodes with hepatosplenomegaly in an 88-year-old female with RA who had taken infliximab and methotrexate (MTX) for six years. Although spontaneous remission occurred following the withdrawal of infliximab and MTX, reversible LPD evolved into hepatosplenic Hodgkin lymphoma without lymphadenopathy presenting as a cholestatic febrile illness. Our findings suggest that the recurrent lesions of MTX-associated LPDs may not always coincide with the primary lesion and may present unexplained findings based on various extranodal diseases.

In obese humans and animals, adiponectin production and release in adipose tissue are downregulated by feedback inhibition, resulting in decreased serum adiponectin. We investigated adiponectin production and release in ventromedial hypothalamic (VMH)-lesioned animals. VMH-lesioned mice showed significant increases in food intake and body weight gain, with hyperinsulinemia and hyperleptinemia at 1 and 4 weeks after VMH-lesioning. Serum adiponectin was elevated in VMH-lesioned mice at 1 and 4 weeks, despite adipocyte hypertrophy in subcutaneous and visceral adipose tissues and increased body fat. Adiponectin production and mRNA were also increased in both adipose tissues in VMH-lesioned mice at 1 week. These results were replicated in VMH-lesioned rats at 1 week. Daily atropine administration for 5 days or subdiaphragmatic vagotomy completely reversed the body weight gain and eliminated the increased adiponectin production and release in these rats, with reversal to a normal serum adiponectin level. Parasympathetic nerve activation by carbachol infusion for 5 days in rats increased serum adiponectin, with increased adiponectin production in visceral and subcutaneous adipose tissues without changes of body weight. These results demonstrate that activation of the parasympathetic nerve by VMH lesions stimulates production of adiponectin in visceral and subcutaneous adipose tissues and adiponectin release, resulting in elevated serum adiponectin.

Summary Objectives Chronic inflammation of periodontitis aggravates glycemic control in type 2 diabetic patients through aggravation of insulin resistance. Increased or decreased release of various inflammatory mediators, such as high sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-6 and adipokines, such as adiponectin, leptin, and resistin, are presumed to be responsible for developing and progressing insulin resistance. The purpose of this study was to examine the effects of periodontal treatment on glycemic control, serum inflammatory mediators and adipokines in type 2 diabetes patients with periodontitis. Methods Twenty-one type 2 diabetic patients with periodontitis received periodontal treatment with topical antibiotics (intervention group) and 8 patients did not receive periodontal treatment (control group). Periodontal examination, including probing pocket depth (PPD) and bleeding on probing (BOP), and blood sampling were performed at baseline, 2 and 6 months after periodontal treatments. Glycated hemoglobin (HbA1c), hs-CRP, TNF-α, IL-6, adiponectin, leptin, and resistin were analyzed. Results In the intervention group, improvements of PPD and BOP, decrease in HbA1c and elevation of serum adiponectin were observed, while in the control group, all parameters were not changed. Generalized linear model revealed that changes of serum adiponectin and TNF-α and change of BOP correlated significantly with the reduction of HbA1c at 6 months after periodontal treatments. Conclusion The results demonstrated that periodontal treatment improves periodontal status and glycemic control with elevation of serum adiponectin in type 2 diabetic patients. The results suggest that HbA1c is reduced by amelioration of insulin resistance due to elevated serum adiponectin after periodontal treatments.

Neuropeptide Y (NPY) is a 36-amino-acid neuropeptide that was first discovered in porcine brain extracts and later in the porcine intestine. It is widely distributed in both the central and peripheral nervous systems and exerts a powerful orexigenic effect. NPY-producing neuronal cell bodies are abundantly localized in the medial arcuate nucleus of the hypothalamus, this being a brain center that integrates signals for energy homeostasis. Accumulated evidence shows that hypothalamic neuropeptides such as ghrelin, orexin, melanin-concentrating hormone (MCH), galanin-like peptide (GALP) and proopiomelanocortin (POMC) are involved in the regulation of feeding behavior and energy homeostasis via neuronal circuits in the hypothalamus. NPY also forms part of the feeding-regulating neuronal circuitry in conjunction with other feeding-regulating peptide-containing neurons within the hypothalamus. We summarize here current knowledge of the neuronal interactions between NPY and the different types of feeding-regulating peptide-containing neurons in the hypothalamus based on evidence at the immunohistochemicl level and with calcium imaging techniques.

Galanin-like peptide (GALP) has an anti-obesity effect in rats and mice. It has been reported that the uptake of GALP by the brain is higher after intranasal administration than with intravenous injection. This study therefore aimed to clarify the effect of intranasal administration of GALP on the feeding behavior of lean and obese mice. Autoradiography revealed the presence of 125I-GALP in the olfactory bulb and the brain microcirculation. The body weights of ob/ob mice gradually increased during vehicle treatment, but remained unchanged in response to repeated intranasal administration of GALP, with both ob/ob and diet-induced obese mice displaying significantly decreased food intake, water intake and locomotor activity when treated with GALP. These results suggest that intranasal administration is an effective route whereby GALP can exert its effect as an anti-obesity drug.

Summary Background We have found previously that ventromedial hypothalamic lesions (VMH) enhance cell proliferation in the visceral organs through vagal hyperactivity in rats. The goal of the current study was to determine the characteristics and nature of cell proliferation in the small intestine in VMH-lesioned mice. Methods The weight and length of the small intestine, thickness of the mucosal and muscle layers, number of proliferating cell nuclear antigen (PCNA)-positive cells, and mitotic cell count in the mucosal layer in VMH-lesioned and Sham VMH-lesioned mice were determined at 7 days after the operation. Results The weight and length of the small intestine in VMH-lesioned mice were significantly greater than those in Sham VMH-lesioned mice, by 11.6% and 15.0%, respectively. The thicknesses of the mucosal and muscle layers of the small intestine in VMH-lesioned mice were also significantly greater than those in Sham VMH-lesioned mice, by 12.7% and 12.5%, respectively. PCNA-positive cells and mitotic cells in the mucosal layer were densely present in crypts in VMH-lesioned mice, and were significantly increased by 31.9% and 71.7%, respectively, compared to Sham VMH-lesioned mice. Conclusions These results demonstrate that VMH lesions in mice enhance cell proliferation in the mucosal layers and cause cell hypertrophy or cell proliferation in the muscle layers of the small intestine, which increases the weight and length of the small intestine. VMH lesions in mice may be a new tool for identifying growth factors and related genes involved in enlarging the small intestine mainly through cell proliferation.

Summary In neural regulation of the endocrine pancreas, there is much evidence to suggest that vagal efferents alter insulin and glucagon secretion, but less information on the effects of vagal afferents. In this study, we investigated the role and function of afferent fibers of the vagus nerve in normal and ventromedial hypothalamic (VMH) lesioned rats with marked hyperinsulinemia. In normal rats, hepatic vagotomy was associated with intraperitoneal (ip) arginine-induced enhancement of insulin and glucagon secretion without an accompanying change in blood glucose levels, ip leucine induced enhancement of insulin secretion accompanied by a decrease in blood glucose levels, and ip alanine-induced enhancement of glucagon secretion accompanied by an increase in blood glucose levels. In VMH lesioned rats with marked hyperinsulinemia, none of these amino acids caused significant changes in insulin and glucagon secretion. We conclude that amino acid sensors in normal rats inhibit excess release of pancreatic hormones induced directly by intake of amino acids, such as that in excess protein ingestion, and maintain blood glucose levels within the normal range. In contrast, in VMH lesioned rats with marked hyperinsulinemia, the function of the amino acid sensors is masked due to the marked hyperinsulinemia in these rats.

Peritoneal dialysis (PD) is an excellent dialysis mo- dality, but it is underutilized in the United States and Japan. In the present study, we evaluated the impact of interventional nephrology in PD on the impres- sions held by patients and nurses about selection of a renal replacement therapy and the complications associated with PD therapy. Over aperiod of 7 years, PD catheter insertion in 120 patients with end-stage renal disease (age: 63.0 ± 13.3 years) was performed by nephrologists at Keio University Hospital or Saitama Medical Center. A questionnaire survey evaluating the advantages and disadvantages of this interventional nephrology approach in PD was distributed to 72 PD patients and to 53 nurses in charge of those patients. After interventional nephrology in PD was adopted, the number of patients selecting PD therapy increased. The incidence of peritonitis was relatively low (1 episode in 101.1 patient-months). Responses to the questionnaire survey showed that neither patients nor nurses were concerned about catheter insertion by physicians, and no communication problems between the patients, nurses, and physicians were reported. Approximately 60% of the nurses specializing in PD therapy showed higher motivation with interventional nephrology, which might have a favorable effect on the selection of PD therapy, on the incidence of peritonitis, and on the tripartite communication between patients, nurses, and physicians.

Liver has a high regenerative capacity and restores its mass and function shortly after partial hepatectomy through increased proliferation and metabolic modification of hepatocytes. The proliferation of hepatocytes can be triggered by its mass reduction after hepatectomy or by the neural factors including lesioning of the ventromedial hypothalamus (VMH). In the present study, we examined the effect of VMH lesioning on liver regeneration in hepatectomized rats by evaluating liver function and morphology. We found that functional deficits caused by partial hepatectomy [prolonged prothrombin time (PT), increased indocyanine green (ICG) retention, and decrease in PAS (periodic Acid-Schiff staining)-positive hepatocytes] were restored by VMH lesioning at 1 week after the surgery, whereas these alterations disappeared at 4 weeks. Morphologically, lipid microdroplets, which are considered to be important for maintaining contiguous liver function via supplying fuel for cell proliferation, were found to accumulate in hepatocytes of the hepatectomized rats at early period (1 day) after partial hepatectomy. Interestingly, such lipid microdroplets were also detected in the VMH lesioned rats and the more abundantly in the VMH lesioned, hepatectomized rats up to 1 week after the surgery. In conclusion, our results suggest that VMH lesioning in rats promotes recovery of liver anatomically and functionally after partial hepatectomy by promoting cell proliferation process.

Summary Objectives Abnormal eating behaviors such as compulsive overeating, eating fast, chewing less, palatable soft food preferences and avoiding hard food are often observed in obese individuals, and these behaviors may affect their masticatory function, but little information of masticatory function in obese subjects are available at present. The present study investigated masticatory function in non-elderly obese Japanese adults and explored the relationships between obesity and masticatory function. Methods Seventy-five obese subjects (BMI ≥ 25; male: 34, female: 41) and 98 subjects with normal weight (BMI 18.5–25; male: 63, female: 35) aged 25–40 years old were enrolled in the present study. The status of masticatory function was determined using a chewing gum mixing method, a direct method of examining masticatory function, and the numbers of present teeth, untreated decayed teeth, missing teeth, and filled teeth were also examined. Results Masticatory function was significantly lower in the obese subjects both in male and female, whereas the numbers of present teeth, decayed teeth, missing teeth and filled teeth did not differ significantly between the obese subjects and the controls both in male and female. Multiple regression analysis revealed a significant correlation between obesity and reduced masticatory function after adjustment for gender, age, and numbers of decayed teeth, missing teeth, and filled teeth. Conclusions Significantly reduced masticatory function was found in male and female non-elderly obese adults based on direct measurement of masticatory function. Multiple regression analysis suggested that obesity might induce reduced masticatory function.

Aims/Introduction: The effects of 5-day voluntary exercise on muscle damage and muscle protein degradation were investigated in a streptozotocin-induced rat model of moderately glycemic, uncontrolled, type 2 diabetes. Materials and Methods: In the preliminary experiment, an oral glucose tolerance (1.0 g/kg) test was carried out to confirm the development of diabetes 3 days after streptozotocin treatment (30 mg/kg). In the genuine experiment, rats were divided into four groups: (i) non-diabetic rats without exercise (controls); (ii) non-diabetic rats with exercise; (iii) diabetic rats without exercise; and (iv) diabetic rats with exercise. After 5 days of voluntary wheel running exercise, blood and 24-h urine were collected, and levels of serum creatine kinase, a marker of muscle damage, and 24-h urinary excretion of muscle degradation products were determined. Results: Type 2 diabetic rats with insulin deficiency that exercised had higher serum creatine kinase and greater urinary excretions of creatinine, urea nitrogen and 3-methylhistidine compared with both type 2 diabetic rats with insulin deficiency and non-diabetic rats that did not exercise. However, there were no differences in serum creatine kinase and urinary excretions of creatinine, urea nitrogen and 3-methylhistidine between non-diabetic rats that did and did not exercise. Conclusions: These findings suggest that muscle damage is induced and muscle protein degradation are enhanced by chronic moderate exercise in moderately glycemic uncontrolled type 2 diabetic rats with insulin deficiency at an intensity level of exercise that does not affect muscle damage and muscle protein degradation in non-diabetic rats. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00130.x, 2011)

Objective: We previously reported that vagal hyperactivity produced by ventromedial hypothalamic (VMH) lesions stimulated cell proliferation of rat pancreatic islet B and acinar cells primarily through a cholinergic receptor mechanism. Methods: This study examined how gene families involved in cell proliferation are regulated after VMH lesions formation. Total pancreatic RNA was extracted, and differences in the gene expression profiles between rats at day 3 after VMH lesioning and sham-VMH-lesioned rats were investigated using DNA microarray and real-time polymerase chain reaction. Results: The VMH lesions regulated the genes that are involved in functions related to cellular growth and proliferation and neuronal development in the pancreas. Real-time polymerase chain reaction also confirmed that gene expressions of angiotensin II receptor-like 1 (AGTRL1) and proline rich 15 (PRR15) were down-regulated at day 3 after the VMH lesions. Conclusions: Ventromedial hypothalamic lesions may change the expression of cell proliferation-related genes and neuron-related genes in a rat pancreas.

The intestinal epithelium is continuously renewed through a balance between cell proliferation and apoptosis. We identified genes of which expression profiles showed significant modulation, and we investigated the cellular mechanisms of this gene regulation in rat intestine after ventromedial hypothalamic (VMH) lesions. Total RNA was extracted, and differences in the gene expression profiles between rats at day 3 after VMH lesioning and in sham-VMH lesioned rats were investigated using DNA microarray analysis and real-time polymerase chain reaction (PCR) methods. DNA microarray analysis revealed that VMH lesions regulated the genes that were involved in functions predominantly related to neuronal development, cell proliferation and apoptosis. Real-time PCR also confirmed that gene expressions of Efnb1 were downregulated. Meanwhile, expression of Casp3 was similar. It is noted that the signaling networks of many gene families, including neuron-specific genes and apoptosis genes in the intestine were changed after VMH lesioning. VMH lesions may suppress mainly the caspase independent type II pathway for apoptosis and induce cell proliferation in the intestine.

New erythropoiesis-stimulating agents with a longer half-life have been developed for the treatment of anemia in patients with end-stage renal disease. This study evaluated the efficacy of darbepoetin alfa (DA) and long-acting epoetin beta pegol (continuous erythropoietin receptor activator, CERA) in patients on peritoneal dialysis (PD). Twenty-nine patients who had undergone PD for at least 6 months and were iron replacement-naïve and negative for inflammatory parameters were enrolled. Hemoglobin (Hgb) levels and blood pressure were evaluated before and after switching from DA to CERA. Percent transferrin saturation (TSAT), serum ferritin levels and blood pressure were also assessed. Twenty-eight patients were subject to the analysis, excluding one patient with a decrease in Hgb by ≥10%. Switching from DA to CERA did not alter Hgb levels. The doses of DA and CERA after 12 month treatment of each agent were 118.48 ± 79.63 and 89.88 ± 47.50 μg/4 weeks, respectively (conversion ratio, 1:0.76). The CERA dose administered during the final 6 months was abated, compared with that given during the initial 6 months (P = 0.035). The frequency of CERA injection over a 12-month period was less than that of DA (10.0 ± 3.0 vs. 16.4 ± 5.0, P 0.01). The conversion from DA to CERA did not alter TSAT, but decreased serum ferritin levels (from 202.69 ± 132.57 to 150.15 ± 110.07 ng/mL, P = 0.012) and systolic blood pressure (from 133.8 ± 17.3 to 129.5 ± 11.3 mm Hg, P = 0.024). In PD patients, lower doses and less frequent injection of CERA are sufficient to maintain Hgb at levels similar to those achieved by DA therapy, with improved iron utilization and reduced blood pressure.

A Japanese woman in her 50s presented with coffee-ground vomiting at a local clinic and was referred to our hospital for further investigation. Esophagogastroduodenoscopy demonstrated a submucosal tumor in the descending part of the duodenum, and she was diagnosed with a gastrointestinal stromal tumor (GIST) by other imaging studies. Elective surgery of the tumor was initially planned. However, on the 13th day of hospitalization, emergency pancreaticoduodenectomy was performed because of massive hematemesis with hemorrhagic shock. Genetic analysis demonstrated a deletion in exon 11 of the c-kit gene, which could dramatically alter the clinical course. Although duodenal GIST with active bleeding is comparatively rare, we have to assume that it is the cause of gastrointestinal bleeding and treat such cases with a minimally invasive surgical procedure and neoadjuvant/adjuvant chemotherapy. It is necessary to accumulate more cases with duodenal GIST to establish an evidence-based therapeutic strategy.

Since we introduced cultured dorsal root ganglia (DRG) neurons from streptozotocin (STZ)-induced diabetic mice as "an in vitro model to study diabetic neuropathy" (Sotelo et al., 1991), more than 30 papers have been devoted to the study of diabetic neuropathy with culture systems of neurons and Schwann cells derived from adult animals. So far, methods for dissociated cell culture of peripheral neurons (mainly DRG neurons) and Schwann cells, and for explant culture of peripheral ganglia and retinas have been applied to diabetic animals or patients. In addition to these diabetic cells, adult animal neurons and Schwann cells cultured under high glucose conditions and adult animal neurons exposed to diabetic serum have been utilized. The findings from these culture models clearly show that the exposure of mature neurons and Schwann cells to hyperglycemic conditions in vivo or in vitro can alter their biophysical and biochemical properties (e.g., cell viability, neurite outgrowth activity, polyol metabolism and electrophysiological features). Therefore, the cultured neurons and Schwann cells can be useful tools for investigating the precise mechanisms leading to diabetic neuropathy and the efficacy of therapeutic agents for the prevention and treatment of that condition.

Cholecystokinin (CCK) plays a major role in the regulation of pancreatic enzyme secretion based on its binding to the CCK-A receptor (CCK-AR). While CCK-AR is known to be expressed in rat islet B cells, the localization of CCK-AR in rat pancreatic A and D cells remains poorly understood. The aim of this study was to identify the localization of CCK-AR in rat pancreatic islets by means of double immunofluorescence straining with antibodies against CCK-AR, glucagon, insulin and somatostatin and with in situ hybridization to detect its transcript. CCK-AR-like immunoreactive cells were found to overlap both with glucagon-like immunoreactive cells and insulin-like immunoreactive cells but not with somatostatin-like immunoreactive cells. An in situ hybridization study using a cRNA probe for CCK-AR revealed that CCK-AR mRNA was expressed in the center and periphery of the pancreatic islets. Further to this, immunofluorecsence staining using anti-glucagon antibody was carried out after in situ hybridization using the CCK-AR cRNA probe in order to identify CCK-AR mRNA expressing cells. CCK-AR mRNA exhibited a distribution pattern almost identical to that of glucagon-like immunoreactive cells. These results show clearly that CCK-AR exists not only in B but also in A cells of the rat pancreas, suggesting that CCK regulates the secretion of insulin and glucagon at least partly via CCK-AR.

1. Sucrose feeding increases the level of stress-induced heat shock protein 70 mRNA in the rat hypothalamus. However, the mechanism by which a sucrose diet induces mRNA remains unclear. The issues investigated in this study were (1) whether a sucrose diet affects nitric oxide production in the hypothalamus, and (2) whether nitric oxide mediates the sucrose and stress-induced elevation of heat shock protein 70 mRNA. 2. To address the first question, we measured the level of nitrate, a final nitric-oxide-oxidation product measurable in vivo, using a microdialysis method. To address the second question, we administered a nitric oxide synthase inhibitor. NG-nitro-L-arginine methyl ester, prior to stress, then measured the mRNA level of heat shock protein 70 by the reverse transcription-competitive polymerase chain reaction method. 3. After the initiation of restraint stress, rats fed a sucrose-containing diet, unlike those fed standard chow, displayed a transient nitrate elevation. This nitrate elevation was attenuated by pretreatment with NG-nitro-L-arginine methyl ester. The mRNA level increases in rats fed a sucrose diet were dose-dependently attenuated by NG-nitro-L-arginine methyl ester. 4. These data suggest that a sucrose diet induces heat shock protein 70 under stress by enhancing nitric oxide production in the hypothalamus.

We demonstrated that ventromedial hypothalamus (VMH) lesions facilitate DNA synthesis, which reflects cell proliferation in abdominal organs, including the liver, pancreas, stomach, small intestine and large intestine, all of which are amply innervated by the vagal nerve.To investigate which area DNA synthesis facilitates and what factors contribute to cell proliferation in the small intestine in VMH-lesioned rats.At 7 days after VMH lesions or sham operations, a segment of rat jejunum was taken for histological examination. A part of the jejunum was also removed from VMH-lesioned and sham-operated rats after 3 days and examined for 5-bromo-2'-deoxyuridine (BrdU) incorporation. At 6, 12 and 24 h after VMH lesions, the proximal intestine was removed from individual rats, from the pylorus to the mid-jejunum. Total RNA was extracted from these tissues of each rat, and the levels of epidermal growth factor (EGF) and transforming growth factor (TGF)-alpha mRNA were determined using reverse-transcription polymerase chain reaction. Cyclooxygenase (COX)-1 and -2 mRNA levels were determined using Northern blotting.: Jejunal villi in VMH-lesioned rats were markedly enlarged compared to those of sham-operated rats and jejunal crypts in VMH-lesioned rats more markedly incorporated BrdU. Northern blot analysis revealed an increase in COX-1 mRNA after 6, 12 and 24 h in the jejunum of VMH-lesioned rats. COX-2 mRNA was decreased 6 and 12 h after VMH lesioning; however, it was significantly increased 24 h after VMH lesions in comparison to sham-operated rats. The levels of EGF and TGF-alpha mRNA were unchanged in VMH lesioned rats.VMH lesions induced enlargement of jejunal villi and increased the gene expression of COX-1 in the small intestine. Prostaglandins, probably E(2), induced by COX-1 may be one candidate factor responsible for the cell proliferation of the small intestinal epithelium in these rats.

Uncoupling proteins (UCPs) are supposed to be involved in diet-induced thermogenesis. Their activities are usually elevated by feeding and reduced by fasting in normal animals. To investigate whether fasting affects the expression of UCPs mRNA in brown adipose tissue (BAT) of bilateral ventromedial hypothalamus (VMH)-lesioned rats, we determined the gene expression of UCP1, UCP2 or UCP3 in BAT of VMH-lesioned rats and examined oxygen consumption in these rats under fed or 48-h fasted conditions. Northern blotting revealed no difference in the expression of UCPs mRNA in BAT between VMH-lesioned and sham-operated rats under the fed condition, however, expressions were increased markedly in BAT of VMH-lesioned rats under the fasted condition. Under the fed condition, no difference in oxygen consumption was observed between VMH-lesioned and sham-operated rats. Under the fasted condition, oxygen consumption decreased in both rats, however, it decreased in VMH-lesioned less than in sham operated rats. To explore the mechanism that fasting elevated BAT UCPs mRNA in VMH-lesioned rats, we measured peroxisome proliferator-activated receptor (PPAR)-gamma mRNA and protein in BAT, because PPAR-gamma agonist can elevate UCPs mRNA levels in BAT. Under the fed condition, no differences in the expression of PPAR-gamma mRNA and protein content were observed between in BAT of VMH-lesioned and sham-operated rats. Under the fasted condition, however, both increased in BAT of VMH-lesioned rats. These results suggest that VMH-lesions enhance the gene expression of UCPs in BAT under long-term fasting as a defensive reaction to inhibit the reduction of body temperature through an increase in PPAR-gamma activity.

In 1997 when WHO initiated the formation of the International Obesity Task Force (IOTF), the Task Force proposed the cut-offs for overweight and obesity as BMI 25 and BMI 30, respectively. If we accept the criteria of BMI ≥ 30 to indicate obesity, it would appear that the prevalence of obesity in Japan of less than 3% has changed little during the last 40 years, and we cannot explain the rapid increase in incidence of obesity-associated chronic diseases such as diabetes, hypertension and hyperlipidemia. Thus, JASSO decided to define BMI ≥ 25 as obesity. This cut-off has been proposed for use in the Asia-Oceania Region, and WHO Western Pacific Region noted this proposal. According to this criterion the prevalence of obesity in Japan would average 20%, with a high of 30% in men over 30 years old, and women over 40 years old. Thus the rates would have increased four times in men and three times in women during these last 40 years. What has caused the increased prevalence of obesity in Japan? Several causes of obesity have been advanced: (i) overeating (ii) errors of eating pattern (iii) inactivity (iv) heredity, and (v) disturbance in thermogenesis. Hyperphagia and inactivity are two major risk factors for obesity. Hyperphagia may be an important factor in individuals. However, the average energy intake in adult people in Japan has not increased; in fact it has declined (2104 kcal/day to 1967 kcal/day) during these 40 years. During this period, the prevalence of obesity has increased three or more times as mentioned above. This indicates that inactivity may be the main cause for the increased incidence of obesity in Japan. Errors of eating pattern (irregular eating, night eating, etc.), including a high proportion of fat to total energy intake (8.7% increased to 26.5%), and a high incidence of β 3-adrenergic polymorphism, might also have contributed to the increased incidence of obesity in Japan.

Mosapride citrate selectively acts on serotonin (5-HT4) receptors, thus accelerating gastrointestinal motility via acetylcholine. However, few studies have evaluated the influence of mosapride citrate on autonomic nervous activity and hemodynamics. Methods: The changes in autonomic nervous activity, QT interval, and QT dispersion resulting from the administration of mosapride citrate were studied. Blood pressure, electrocardiograms (ECGs), percutaneous electrogastrograms (EGGs), and ultrasonography were recorded in 20 healthy adult volunteers before and after mosapride citrate (10 mg) was administered. Autonomic nervous activity was evaluated by spectral analyses of heart rate and blood pressure variabilities. Serial changes in low-frequency components (LF, 0.04–0.15 Hz), high-frequency components (HF, 0.15–0.40 Hz), and the LF/HF ratio were investigated. Results: The mean peak power of EGG increased significantly, from 86 ± 34 μV to 131 ± 49 μV, after the administration of mosapride citrate (P < 0.05). Gastric emptying significantly increased after the administration of mosapride citrate (P < 0.05). However, neither blood pressure nor heart rate changed significantly after the drug was administrated. In addition, spectral analyses of heart rate and blood pressure variabilities showed no significant changes in autonomic nervous activity parameters, QT intervals, or QT dispersions. Conclusions: Mosapride citrate increased gastric motility and emptying without influencing autonomic nervous activity, suggesting that it may be very useful for elderly patients or patients with autonomic imbalance.

Orexin-A and -B are hypothalamic neuropeptides that have been implicated in stimulating food intake and maintaining arousal. Because food intake is closely related to the control of energy homeostasis, we examined the effects of intracerebroventricular administration of orexins on O 2 consumption (VO 2 ), an index of energy expenditure, body temperature, skin temperature and heart rate (HR) in urethane-anesthetized rats. VO 2 increased significantly after an orexin-A injection, and this increase was accompanied by a significant tachycardiac response. Orexin-B also increased VO 2 and HR, although orexin-A was ~30 times more potent in eliciting these responses than orexin-B. The effects of orexin-A were dose dependent over the range of 1 pmol–1 nmol, whereas an injection of the saline vehicle had no effect. These findings suggest that centrally acting orexin-A functions to increase energy expenditure.

(1) Administration of resiniferatoxin (RTX; 50 μg/kg, s.c.) induced triphasic metabolic responses with immediate facilitation followed by transitory inhibition and subsequent long-lasting facilitation in urethan-anesthetized rats. The temperature of skin increased immediately after the RTX injection, suggesting cutaneous vasodilation and heat loss. The colonic temperature decreased initially and then increased above the baseline level. (2) Pretreatment with ruthenium red, a putative vanilloid receptor (VN 2 ) antagonist, attenuated the RTX-induced heat loss and inhibition of heat production. (3) Adrenal demedullation selectively attenuated the RTX-induced immediate thermogenesis, and the β -blocker propranolol prevented both phases of thermogenesis. Thus, the sympathetic nervous system and adrenaline contributed to the thermogenic responses.

We investigated the efficacy of a 4-wk supplementation of conjugated linoleic acid (CLA) as free fatty acid (FFA) or triacylglycerol (TG) on serum leptin concentration, body-fat accumulation, and mitochondrial β-oxidation in Otsuka Long-Evans Tokushima Fatty (OLETF) rats. A significant reduction of serum leptin concentration (42%) and a decrease in the wet weights of perirenal, epididymal, and omental/visceral-adipose tissue in TG-CLA and FFA-CLA groups were found in comparison with the OLETF control group. Both forms of CLA supplementation produced a 5.2% decrease in body weight compared with the control even though food intake was similar in the OLETF groups. Moreover, both forms of CLA enhanced carnitine-palmitoyltransferase activity in brown adipose tissue, perirenal adipose tissue, red gastrocnemius muscle, and liver in comparison with the OLETF control group. Serum concentrations of non-esterified fatty acid and TG also were reduced in rats fed diets supplemented with TG-CLA and FFA-CLA.

The study investigated the usefulness of three-dimensional helical computed tomography (3D-CT) before laparoscopic cholecystectomy (LSC) when compared with that of endoscopic retrograde cholangiography (ERC). Forty-five patients referred for LSC, who had undergone 3D-CT cholangiography and ERC simultaneously, participated in the study. Endoscopic retrograde cholangiography and 3D-CT cholangiography were compared in each patient with regard to opacification of the biliary tree, stones, and anatomic variations. Three-dimensional helical CT cholangiography and ERC imaging for predicting operative difficulties in LSC also were compared. The common bile duct and cystic duct were shown in the patients by the images, but the gallbladder was shown in 43 patients (96%) with use of 3D-CT cholangiography and in 36 patients (80%) with use of ERC. A third or more peripheral branches were shown completely with use of 3D-CT cholangiography in 33 patients (73%) and in 32 patients (71%) with use of ERC. Cystic duct stones were found in two of three patients with use of 3D-CT cholangiography and ERC. Common bile duct stones in five of seven patients were detected with use of 3D-CT cholangiography, but all of the common bile duct stones were detected with use of ERC. Anatomic variations of the bile duct were shown in three of four patients by 3D-CT cholangiography and in all patients with use of ERC. No significant differences in findings of the angle of bifurcation and presence of Heister valves between operative easy and complex cases were shown by 3D-CT cholangiography and ERC, despite the more accurate assessment of the cystic duct anatomy with use of 3D-CT cholangiography than with use of ERC. Three-dimensional helical CT cholangiography is useful clinically in preoperative assessment of biliary anatomy, but it is not reliable in the detection of common bile duct stones, and it is not helpful in predicting technical difficulty during LSC.

Ascorbic acid (AA) is a naturally occurring major antioxidant that is essential for the scavenging of toxic free radicals in both plasma and tissues. AA levels in plasma and tissues have been reported to be significantly lower than normal in diabetic animals and humans, and might contribute to the complications found at the late stages of diabetes. In this study, plasma and hepatic AA levels and AA regeneration were studied in the Goto–Kakizaki diabetic rat (GK rat) to elucidate the mechanism of decreasing plasma and hepatic AA levels in diabetes. AA concentrations in the plasma and liver were significantly lower in GK than in control rats. AA levels in primary cultured hepatocytes derived from GK rats were lower than those derived from control Wistar rats with or without dehydroascorbic acid (DHA) in the medium. Among various enzyme activities that reduce DHA to AA, the NADPH-dependent regeneration of AA in the liver was significantly suppressed in GK rats. Northern blot analysis revealed that only the expression of 3-α-hydroxysteroid dehydrogenase (AKR) was significantly suppressed in these rats. These results suggest that decreased AA-regenerating activity, probably through decreased expression of AKR, contributes to the decreased AA levels and increased oxidative stress in GK rats.

Systemic administration of capsaicin elicits heat production, which can be observed in decerebrated preparations but is blocked by spinal transection. To identify the critical locus involved in the capsaicin-induced thermogenesis in the brainstem, we studied the effect of capsaicin on rats with bilateral electrolytic lesions in the premotor areas of sympathoadrenal preganglionic neurons. Lesions in the rostral ventrolateral medulla (RVLM), but not in other regions, largely attenuated the capsaicin-induced heat production. Unilateral microinjection of 30-100 nl capsaicin (0.5%, w/v) into the RVLM elicited a heat production response, whereas capsaicin injection in neighboring areas or vehicle injection into the RVLM did not affect heat production. These results suggest that the thermogenic effect of capsaicin is mediated, at least in part, by some capsaicin-sensitive structure in the RVLM.

OBJECTIVE: To investigate the inhibitory effects of CT-II, extract of Nomame Herba, on lipase activity in vitro and on obesity in rats fed a high-fat diet in vivo. DESIGN: The assay for the inhibitory effect of CT-II on lipase activity was performed by measuring released free fatty acids after the incubation of the medium with CT-II, porcine pancreatic lipase and triolein (experiment 1). In vivo experiments, lean rats or obese rats (570–718 g) were fed a high-fat diet containing 60% fat with or without CT-II for 8 weeks (experiment 2), for 14 days (experiment 3) or for 12 weeks (experiment 4), respectively. MEASUREMENT: The time course of body weight, food intake, organ weight (parametrial fat, liver, heart and kidney) and plasma parameters (triglyceride, total cholesterol, glucose, AST, ALT and insulin), fecal output of total fat and total cholesterol were measured. Hepatic histological examinations were also performed. RESULTS: CT-II inhibited the porcine lipase activity dose-dependently in vitro (experiment 1). Body and liver weight were reduced and hepatic histological examination showed an amelioration of fatty liver in CT II treated animals (experiment 2). CT-II significantly inhibited body weight gain and plasma triglyceride elevation in a dose-dependent manner, without affecting food intake in lean rats fed the high-fat diet. Elevated plasma AST and ALT were also decreased (experiment 3). When obese rats fed the high-fat diet were treated with CT-II for up to 6 months, body weight was initially reduced and thereafter weight gain was significantly suppressed. Total body fat was also significantly reduced and significant reduction of plasma AST and ALT was observed (experiment 4). CONCLUSIONS: These results demonstrated that the lipase inhibitor CT-II is effective in preventing and ameliorating obesity, fatty liver and hypertriglyceridemia in rats fed a high-fat diet.

To determine the influence of dietary fructose and glucose on circulating leptin levels in lean and obese rats, plasma leptin concentrations were measured in ventromedial hypothalamic (VMH)-lesioned obese and sham-operated lean rats fed either normal chow or fructose- or glucose-enriched diets (60% by calories) for 2 wk. Insulin resistance was evaluated by the steady-state plasma glucose method and intravenous glucose tolerance test. In lean rats, glucose-enriched diet significantly increased plasma leptin with enlarged parametrial fat pad, whereas neither leptin nor fat-pad weight was altered by fructose. Two weeks after the lesions, the rats fed normal chow had marked greater body weight gain, enlarged fat pads, and higher insulin and leptin compared with sham-operated rats. Despite a marked adiposity and hyperinsulinemia, insulin resistance was not increased in VMH-lesioned rats. Fructose brought about substantial insulin resistance and hyperinsulinemia in both lean and obese rats, whereas glucose led to rather enhanced insulin sensitivity. Leptin, body weight, and fat pad were not significantly altered by either fructose or glucose in the obese rats. These results suggest that dietary glucose stimulates leptin production by increasing adipose tissue or stimulating glucose metabolism in lean rats. Hyperleptinemia in VMH-lesioned rats is associated with both increased adiposity and hyperinsulinemia but not with insulin resistance. Dietary fructose does not alter leptin levels, although this sugar brings about hyperinsulinemia and insulin resistance, suggesting that hyperinsulinemia compensated for insulin resistance does not stimulate leptin production.

L-アラビノースは小腸スクラーゼを特異的に阻害し, ショ糖の消化吸収を抑制する。実験動物ではショ糖負荷後の血糖上昇を用量依存的に抑制することが認められている。本研究では, ヒトにおけるショ糖含有食品摂取後の血糖上昇およびインスリン分泌に及ぼすL-アラビノース添加の効果を, 健常者 (48例) および2型糖尿病患者 (10例) で検討した。試験はクロスオーバー法または群間比較試験で行った。その結果, (1) 健常者 (8例) を対象にショ糖50gを摂取させた試験で, L-アラビノース添加ショ糖摂取群では血糖値および血中インスリン値の上昇が有意に抑制された。(2) 健常中高年 (40例) を対象にショ糖含有食品 (ゼリー: ショ糖含有量30g) を摂取させた試験で, L-アラビノース添加群では血糖値の上昇が添加濃度に依存して抑制された。(3) 2型糖尿病患者を対象とした試験でも, L-アラビノース添加ショ糖の有用性が認められた。(4) すべての試験において消化器症状等の副作用は認められなかった。以上より, L-アラビノースは健常者および2型糖尿病患者において安全にショ糖摂取後の血糖上昇を抑制することが明らかになった。

Background Body temperature is usually regulated by opposing controls of heat production and heat loss. However, systemic administration of capsaicin, the pungent ingredient of hot peppers, facilitated heat production and heat loss simultaneously in rats. We recently found that the capsaicin-induced heat loss and heat production occur simultaneously and that the biphasic change in body temperature is a sum of transient heat loss and long-lasting heat production. Moreover, suppression of the heat loss response did not affect capsaicin-induced heat production and suppression of heat production did not affect capsaicin-induced heat loss. These observations suggest the independent peripheral mechanisms of capsaicin-induced thermal responses. Thus, the capsaicin-induced thermal responses apparently lack an integrated control. Methods Male Wistar rats were maintained at an ambient temperature of 24 +/- 1 degrees C on a 12 h on-off lighting schedule at least for two weeks before the experiments. They were anesthetized with urethane (1.5 g/kg, i.p.) and placed on a heating pad, which was kept between 29 and 30 degrees C. Skin temperature(Ts) was measured with a small thermistor, which was taped to the dorsal surface of the rat's tail, to assess vasoactive changes indirectly. Colonic temperature(Tc) was measured with another thermistor inserted about 60 mm into the anus. O2 consumption was measured by the open-circuit method, and values were corrected for metabolic body size (kg0.75). Capsaicin (Sigma) was dissolved in a solution comprising 80% saline, 10% Tween 80, and 10% ethanol, and injected subcutaneously at a dose of 5 mg/kg. Each rat received a single injection of capsaicin because repeated administration of capsaicin renders an animal insensitive to the subsequent administration of capsaicin. Laminectomy was performed at the level of the first and second cervical vertebrae to expose the cervical spinal cord for sectioning. The brain was transected at 4-mm rostral from the interaural line with an L-shaped knife. Results After administration of capsaicin, O2 consumption increased from 13.5 +/- 0.4 mL/min/kg0.75 at 0 min to a peak of 15.9 +/- 0.4 mL/min/kg0.75 at 71 min and gradually declined but remained higher than the basal value until the end of the 4-h observation period. Ts also immediately increased from 27.7 +/- 0.2 degrees C to 31.9 +/- 0.3 degrees C at 39 min, and it returned to the baseline level within 90 min after the capsaicin administration. Tc initially decreased from 37.1 +/- 0.1 degrees C to 36.8 +/- 0.2 degrees C at 43 min and then gradually increased over the baseline level and remained at 37.6 +/- 0.2 degrees C until the end of the experiment. In spinalized rats, the capsaicin-induced increases in O2 consumption was largely attenuated, while the basal O2 consumption was similar to that of control rats. The basal Ts of spinalized rats was 32.4 +/- 0.3 degrees C, which was higher than that of control rats. Capsaicin increased Ts by less than 1 degree C, and Tc did not change after the capsaicin administration. O2 consumption of decerebrated rats was statistically higher than that of control rats after the injection of capsaicin. However, capsaicin did not increase Ts, showing a lack of a vasodilatory response. Decerebration between the hypothalamus and midbrain prevented the capsaicin-induced heat loss but not the heat production response. Conclusion These results show that the capsaicin-induced heat production and heat loss are controlled separately by the brainstem and by the forebrain, respectively, and suggest that the body temperature regulation is performed without an integrative center.

There are no reports that hypothalamus can directly affect the expression of neuron-related genes and immune-related genes in liver. We identified genes of which expression profiles showed significant modulation in rat liver after ventromedial hypothalamic (VMH) lesions. Total RNA was extracted, and differences in the gene expression profiles between rats at day 3 after VMH lesioning and sham-VMH lesioned rats were investigated using DNA microarray analysis. The result revealed that VMH lesions regulated the genes that were involved in functions related to neuronal development and immunofunction in the liver. Real-time PCR also confirmed that gene expression of SULT4A1 was upregulated, but expression of ACSL1 and CISH were downregulated at day 3 after VMH lesions. VMH lesions may change the expression of neuron-related genes and immune-related genes in rat liver.

Tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance in obese subjects, through its overexpression in fat tissue. However, how exercise can modify the expression of TNF-alpha is controversial. We examined TNF-alpha in adipose tissue using an animal model of insulin resistance that was produced by feeding rats a diet high in sucrose. The rats were allocated to one of three groups: those receiving a starch-based diet (control group): those fed a high-sucrose diet (sucrose-fed group): and those fed a high-sucrose diet and given wheel exercise (exercised group). The animals were allowed to eat and drink ad lib for 4 or 12 weeks (4 wk: control n=7, sucrose-fed n=7, exercised n=10; 12 wk: control n=5, sucrose-fed n=5, exercised n=9). The voluntary wheel exercise was initiated with the feeding of the high-sucrose diet. The rats in the exercise groups ran 15 +/- 3 km/week. We showed that 12-week voluntary running exercise significantly (P

Unilateral microinjection of calcitonin gene-related peptide (CGRP, 1.6 pmol; 0.2 microl) into the ventromedial hypothalamus (VMH) and dorsomedial hypothalamus (DMH) immediately increased oxygen consumption (VO2), heart rate (HR), colonic temperature (Tco), and temperature of interscapular brown adipose tissue (TIBAT) in urethane-anesthetized rats, whereas vehicle saline injection into the VMH and CGRP injection into other hypothalamic regions such as the preoptic area, lateral hypothalamic area, paraventricular nucleus, and bed nucleus of the stria terminalis had no effect. The effects of CGRP injection into the VMH were dose-dependent over the range of 0.016-1.6 pmol. CGRP administration to the lateral ventricle (LV) required 16-320 pmol to elicit similar degrees of responses that were observed after the injection into the VMH. The increase in TIBAT was always higher than that in Tco after CGRP injection. Injection of [Cys(ACM)2,7]hCGRPalpha, a selective CGRP2 receptor agonist, did not induce any thermogenic effects. Human CGRP8-37, a proposed CGRP1 receptor antagonist, by itself induced heat production responses with no signs of inhibition of CGRP-induced responses. Thus, the receptor subtype of the thermogenic effect of CGRP could not be determined by the available pharmacological tools. The present results show that centrally administrated CGRP induces heat production in the BAT specifically through the VMH or DMH.

To explore the role of adiposity on hypertriglyceridemia associated with obesity, we examined the relation between triglyceride secretion rate (TGSR) and plasma leptin, insulin, or insulin resistance in ventromedial hypothalamus (VMH)-lesioned rats in the dynamic and static phases (2 and 14 wk after lesions, respectively). VMH-lesioned rats gained body weight (BW) at fivefold higher rates in the dynamic phase compared with sham-operated control (sham) rats, and BW gain reached a plateau in the static phase. Parametrial fat pad mass was increased 2.5-fold in VMH-lesioned rats compared with sham rats in both phases. Leptin levels were sixfold higher in VMH-lesioned rats of the dynamic phase and even higher in the static phase. Insulin levels were twofold higher in VMH-lesioned rats than in sham rats in both phases. In the dynamic phase, VMH-lesioned rats had 2-fold higher plasma triglyceride (TG) levels and 2.6-fold higher TGSRs, whereas steady-state plasma glucose (SSPG) values, an indicator of insulin resistance, were lower. SSPG values became significantly higher in VMH-lesioned rats in the static phase, but TGSR was not further accelerated. TGSR was significantly associated with leptin, independent of insulin. Leptin was highly correlated with BW, fat mass, and nonesterified fatty acids (NEFA). These results suggest that adiposity itself plays a critical role in TGSR probably through increased NEFA flux from enlarged adipose tissues. Insulin resistance is not associated with the overproduction of TG in this animal model for obesity.