Effects of food deprivation on the hypothalamic feeding-regulating peptides gene expressions in serotonin depleted rats.

We examined the effects of serotonin (5-HT) depletion induced by peripheral injection of 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA) on the expression of feeding-regulating peptides expressions by using in situ hybridization histochemistry in adult male Wistar rats. PCPA pretreatment had no significant effect on basal levels of oxytocin, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), pro-opiomelanocortin (POMC), cocaine and amphetamine-regulated transcript (CART), neuropeptide-Y (NPY), agouti-related protein (AgRP), melanin-concentrating hormone (MCH) or orexin in the hypothalamus. Food deprivation for 48 h caused a significant decrease in CRH, TRH, POMC, and CART, and a significant increase in NPY, AgRP and MCH. After PCPA treatment, POMC and CART did not decrease despite food deprivation. NPY was significantly increased by food deprivation with PCPA, but was attenuated compared to food deprivation without PCPA. These results suggest that the serotonergic system in the hypothalamus may be involved in the gene expression of POMC, CART, and NPY related to feeding behavior.

The dipeptidyl peptidase-4 inhibitor des-fluoro-sitagliptin regulates brown adipose tissue uncoupling protein levels in mice with diet-induced obesity.

OBJECTIVE: Dipeptidyl peptidase (DPP)-4 is responsible for the degradation of several peptides that contain an alanine or proline at the penultimate position or position P1. DPP-4 inhibitors (DPP-4is) have protective effects against type-2 diabetes and several metabolic disorders. METHODS: In the present study, we examined the effects of des-fluoro-sitagliptin (DFS), a DDP-4i, on body adiposity and levels of peroxisome proliferator-activated receptor (PPAR)-α, PPAR-γ coactivator-1 (PGC-1), and uncoupling proteins (UCPs) in mice with diet-induced obesity. RESULTS: Treatment with DFS dose-dependently decreased the weight of white adipose tissue and serum levels of glucose, compared with controls, without influencing food intake (P<0.05). Additionally, DFS treatment increased the levels of PPAR-α, PGC-1, and UCPs in brown adipose tissue (BAT), and of PPAR-α and UCP3 in skeletal muscle (P<0.05). Furthermore, the effects on BAT PGC-1 and muscle PPAR-α levels were attenuated by treatment with the glucagon-like peptide 1 (GLP-1) antagonist exendin (9-39). Interestingly, hypothalamic levels of proopiomelanocortin (POMC) were increased by DFS treatment and the effects of DFS on PPAR-α, PGC-1, and UCP levels were attenuated in melanocortin (MC)-4 receptor-deficient mice. CONCLUSIONS: In conclusion, high-dose DFS appeared to regulate body adiposity and UCPs in mice with diet-induced obesity, at least partly through a GLP-1 and/or MC-4 pathway.

The gene expression of the hypothalamic feeding-regulating peptides in cisplatin-induced anorexic rats.

Cisplatin has been widely used; however, various disadvantageous side effects afflict patients. Rikkunshito (RKT), a traditional Japanese herbal medicine, has been widely prescribed in Japan to improve anorexia; but the mechanisms are unknown. Here we studied whether RKT could improve anorexia induced by cisplatin and changes in feeding-regulating peptides in the hypothalamus in rats. Adult male rats were divided into 4 groups: water+saline (WS), water+cisplatin (WC), RKT+saline (RS), and RKT+cisplatin (RC) groups. Water or RKT (1g/kg) was intragastrically administered for 4 days, from day -1 to day 2, and saline or cisplatin (6mg/kg) was intraperitoneally (i.p.) administered at day 0. After i.p. administration, cumulative food intake, water intake, urine volume and body weight were measured. The rats were then decapitated, followed by removal of the brain, and feeding-regulating peptides in the hypothalamus were measured by in situ hybridization histochemistry. In the three-day measurements, there were no significant changes in cumulative water intake and urine volume. The body weight and cumulative food intake in WC significantly decreased compared to WS, whereas these were not observed in RC. Pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) in the arcuate nucleus (ARC) in WC significantly increased, and neuropeptide Y (NPY) in the ARC decreased compared to WS, whereas those in RS and RC were comparable to WS. These results suggest that RKT may have therapeutic potential for anorexia induced by cisplatin.

Brain-derived neurotrophic factor, corticotropin-releasing factor, and hypothalamic neuronal histamine interact to regulate feeding behavior.

Brain-derived neurotrophic factor (BDNF), corticotropin-releasing factor (CRF), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among BDNF, CRF, and histamine during the regulation of feeding behavior in rodents. Food intake was measured after treatment with BDNF, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), or CRF antagonist. We measured food intake in wild-type mice and mice with targeted disruption of the histamine H1 receptor (H1KO mice) after central BDNF infusion. Furthermore, we investigated CRF content and histamine turnover in the hypothalamus after BDNF treatment, and conversely, BDNF content in the hypothalamus after histamine treatment. We used immunohistochemical staining for histamine H1 receptors (H1-R) in BDNF neurons. BDNF-induced feeding suppression was partially attenuated in rats pre-treated with FMH or a CRF antagonist, and in H1KO mice. BDNF treatment increased CRF content and histamine turnover in the hypothalamus. Histamine increased BDNF content in the hypothalamus. Immunohistochemical analysis revealed that H1-Rs were expressed on BDNF neurons in the ventromedial nucleus of the hypothalamus. These results indicate that CRF and hypothalamic neuronal histamine mediate the suppressive effects of BDNF on feeding behavior and body weight.

Initial Japanese experience with the LAP-BAND system.

INTRODUCTION: Laparoscopic bariatric surgery has gradually spread in Japan since it was introduced in 2000. In 2005, we introduced laparoscopic adjustable gastric banding (LAGB) with the LAP-BAND system into Japan. Here, we evaluate our intermediate-term results with the LAP-BAND system. METHODS: Between August 2005 and June 2010, 27 Japanese patients with morbid obesity (BMI ≥ 35 kg/m(2) ) underwent LAGB with the LAP-BAND system in our institution. Our patients' average weight was 111 kg and BMI was 41 kg/m(2) . All LAGB procedures were performed through the pars flaccida pathway with band fixation using gastric-to-gastric sutures. The average follow-up period was 48 months. RESULTS: All procedures were completed laparoscopically. One early complication (sudden cardiac arrest due to postoperative bleeding) and three late complications (port trouble, megaesophagus, and band slippage) were experienced, and reoperations were performed in three of the patients. Weight loss and percentage of excess weight loss on average were 26 kg and 53% after 3 years and 22 kg and 53% after 6 years, respectively. In line with this good weight loss, comorbidities, especially those of type 2 diabetes and metabolic syndrome were frequently resolved or improved. CONCLUSION: LAGB with the LAP-BAND system appears to be beneficial in obese Japanese patients.

Cilnidipine regulates glucose metabolism and levels of high-molecular adiponectin in diet-induced obese mice.

The aim of the present study is to examine the effects of the antihypertensive drug cilnidipine on glucose metabolism and adipocytokines, including adiponectin, in diet-induced obese (DIO) mice. The effects of cilnidipine on insulin sensitivity and the levels of adiponectin in DIO mice were examined after the mice had been treated with cilnidipine dissolved in water at a dose of 0.2 g l(-1) for 14 days. As expected, treatment with cilnidipine decreased the systolic and diastolic blood pressures in DIO mice, compared with control mice (P<0.05 for each parameter). Cilnidipine treatment improved glucose and insulin sensitivity in DIO mice. In addition, cilnidipine treatment dramatically increased the level of adiponectin in white adipose tissue (P<0.05) and the circulating levels of total and high-molecular weight (HMW) adiponectin in DIO mice (P<0.01 for each parameter). Furthermore, the secretion of HMW adiponectin and the ratio of HMW adiponectin/total adiponectin were both increased after cilnidipine treatment. Finally, the secretion of adiponectin from adipocytes was increased after cilnidipine treatment. Taken together, these results indicate that cilnidipine improves insulin tolerance and adiponectin levels, especially high-molecular type adiponectin, in DIO mice.

Nesfatin-1, corticotropin-releasing hormone, thyrotropin-releasing hormone, and neuronal histamine interact in the hypothalamus to regulate feeding behavior.

Nesfatin-1, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and hypothalamic neuronal histamine act as anorexigenics in the hypothalamus. We examined interactions among nesfatin-1, CRH, TRH, and histamine in the regulation of feeding behavior in rodents. We investigated whether the anorectic effect of nesfatin-1, α-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), a CRH antagonist, or anti-TRH antibody affects the anorectic effect of nesfatin-1, whether nesfatin-1 increases CRH and TRH contents and histamine turnover in the hypothalamus, and whether histamine increases nesfatin-1 content in the hypothalamus. We also investigated whether nesfatin-1 decreases food intake in mice with targeted disruption of the histamine H1 receptor (H1KO mice) and if the H1 receptor (H1-R) co-localizes in nesfatin-1 neurons. Nesfatin-1-suppressed feeding was partially attenuated in rats administered with FMH, a CRH antagonist, or anti-TRH antibody, and in H1KO mice. Nesfatin-1 increased CRH and TRH levels and histamine turnover, whereas histamine increased nesfatin-1 in the hypothalamus. Immunohistochemical analysis revealed H1-R expression on nesfatin-1 neurons in the paraventricular nucleus of the hypothalamus. These results indicate that CRH, TRH, and hypothalamic neuronal histamine mediate the suppressive effects of nesfatin-1 on feeding behavior.

Obesity-related chronic kidney disease is associated with spleen-derived IL-10.

BACKGROUND: Obesity is associated with systemic low-grade inflammation and is a risk factor for chronic kidney disease (CKD), but the molecular mechanism remains uncertain. We noticed spleen-derived interleukin (IL)-10 because it is observed that obesity reduces several cytokines in the spleen. METHODS: We examined whether spleen-derived IL-10 regulates CKD caused by a high-fat diet (HF)-induced obesity as follows: (i) male mice were fed with HF (60% fat) during 8 weeks and IL-10 induction from the spleen was examined, (ii) glomerular hypertrophy, fibrosis, inflammatory responses in the kidney and systolic blood pressure (SBP) were evaluated in splenectomy (SPX)-treated mice fed HF, (iii) exogenous IL-10 was systemically administered to HF-induced obese mice and the alteration of obesity-induced pathogenesis caused by IL-10 treatment was assessed. (iv) IL-10 knockout (IL-10KO) mice were treated with SPX and glomerular hypertrophy, fibrosis and the inflammatory condition in the kidney and SBP were also investigated. RESULTS: Obesity decreased serum levels of only IL-10, an anti-inflammatory cytokine even though pro- and anti-inflammatory cytokine expression in the spleen was significantly lower in the obese group. SPX aggravated HF-induced inflammatory responses in the kidney and hypertension. These HF-induced alterations were inhibited by systemically administered IL-10. Moreover, SPX had little effect on inflammatory responses and SBP in the kidney of IL-10KO mice. CONCLUSIONS: We suggest that obesity reduces IL-10 induction from the spleen, and spleen-derived IL-10 may protect against the development of CKD induced by obesity.

High alanine aminotransferase level as a predictor for the incidence of macrovascular disease in type 2 diabetic patients with fatty liver disease.

PURPOSE: We investigated whether fatty liver (FL) disease in type 2 diabetic mellitus (T2DM) patients affects their incidence of macrovascular disease. In addition, we detected a useful marker for predicting the incidence of macrovascular disease events. METHODS: A total of 458 patients who underwent abdominal ultrasonography (US) between April 2003 and March 2004 in a diabetic clinic were divided into FL (n = 211) and non-FL (NFL; n = 247) groups, and followed by a diabetologist and/or hepatologist for 5 years. RESULTS: No significant difference in the incidence of macrovascular disease, neither cerebrovascular disease nor coronary heart disease, was observed between FL and NFL patients. Interestingly, in FL diabetic patients, only an alanine aminotransferase (ALT) level ≥30 IU/l was significantly associated with the incidence of macrovascular events in univariate (odds ratio [OR], 10.632; 95 % confidence interval [CI], 1.302-86.841; p = 0.0274) and multivariate (OR, 10.134; CI 1.223-83.995; p = 0.0318) analyses. Patients with higher ALT levels had a higher cumulative incidence of macrovascular disease events than did those with lower ALT levels (p = 0.0068). In conclusion, an ALT level ≥30 IU/l is an independent risk indicator of macrovascular disease in diabetic patients with FLD, whereas the presence of FL itself in T2DM patients is not associated with an increased incidence of macrovascular events. CONCLUSIONS: Our findings indicate that therapeutic interventions may be necessary for FL patients with high ALT levels to prevent macrovascular disease.

A novel anti-inflammatory role for spleen-derived interleukin-10 in obesity-induced inflammation in white adipose tissue and liver.

Obesity is associated with systemic low-grade inflammation and obesity-related metabolic disorders. Considering that obesity decreases the expression of proinflammatory cytokines in the spleen, we assessed the role of interleukin (IL)-10, an anti-inflammatory cytokine produced by the spleen, in the pathogenesis of obesity. Changes in obesity-related pathogenesis, including inflammatory responses in multiple organs, were assessed after systemic administration of exogenous IL-10 to splenectomy (SPX)-treated obese wild-type and IL-10 knockout (IL-10KO) mice. Obesity resulted in the inability of the spleen to synthesize cytokines, including IL-10, and proinflammatory cytokines in obesity are then likely to emerge from tissues other than the spleen because serum levels of IL-10, but not proinflammatory cytokines, decreased despite the expression of these cytokines in the spleen being reduced in high fat-induced obese mice. SPX aggravated the inflammatory response in white adipose tissue (WAT) and the liver and suppressed adiposity in WAT. However, it accentuated adiposity in the liver. These SPX-induced changes were inhibited by systemic administration of IL-10. Moreover, SPX had little effect on the inflammatory responses in WAT and the liver of IL-10KO mice. These data show the role of spleen-derived IL-10 in diet-induced changes as a result of inflammatory responses in WAT and the liver.

Role of the spleen in the development of steatohepatitis in high-fat-diet-induced obese rats.

Obesity is considered a systemic low-grade inflammatory state. Although the spleen is the main immune organ with a close anatomical relationship with the liver, its role in the progression of fatty liver disease remains uncertain. Therefore, we sought to clarify the functional role of the spleen in the development of steatohepatitis in high-fat (HF)-diet-induced obese rats. Male Sprague-Dawley rats were fed HF food and divided into two groups, a splenectomy (SPX) group and a sham-operation (Sham) group. The liver and abdominal white adipose tissue (WAT) were removed one and six months after surgery, and we evaluated the effects of SPX on WAT and HF-induced fatty liver. SPX rats exhibited worse dyslipidemia and inflammatory changes in WAT one month after surgery. Hepatic steatosis and inflammation were accelerated by SPX, based on the time after surgery. At one month after surgery, the tissue triglyceride content increased in SPX rats, compared with Sham controls (P < 0.05). The liver histology also showed a worsening of steatosis in those rats. At six months after SPX, dramatic inflammatory and fibrotic changes were observed in liver tissue sections. Hepatic carnitine palmitoyltransferase-1 was suppressed at one and six months after SPX (P < 0.05 for each). WAT and liver tissue levels of inflammatory markers such as tumor necrosis factor-α, and the expression of Kupffer cells were all increased at six months in SPX rats, compared with Sham controls (P < 0.05 for each). Our results indicate that the preservation of the spleen contributes to the prevention of the progression of hepatic steatosis to steatohepatitis in obese rats.

Association between hippocampal volume and serum adiponectin in patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus (DM) is associated with cognitive dysfunction and hippocampus volume. The aim of the present study was to test the hypothesis that the level of the adipocytokine adiponectin correlates with hippocampus volume and insulin resistance in patients with type 2 DM. A total of 45 patients with type 2 DM were divided into two groups: a low adiponectin group and a normal adiponectin group. Hippocampus volume was measured by computer-assisted analysis using a magnetic resonance imaging (MRI) voxel-based specific regional analysis system developed for the study of Alzheimer's disease as the end point for assessment of hippocampus volume. Mean hippocampus volume was lower in the low adiponectin group than in the normal adiponectin group (P<.0001). Fasting serum concentrations of glucose (P<.05) and insulin (P<.0001), and homeostasis model assessment index (P<.0001), were all higher in the low adiponectin group than in the normal adiponectin group. Multiple regression analysis showed that hippocampus volume independently predicted serum adiponectin level. These results suggest that circulating levels of adiponectin are related to hippocampus volume in patients with type 2 DM.

Intracerebroventricular administration of urotensin II regulates food intake and sympathetic nerve activity in brown adipose tissue.

To clarify the functional roles of urotensin II in regulating energy balance, we investigated the effects of a central infusion of urotensin II on food intake, uncoupling protein (UCP) 1 mRNA expression, temperature, and sympathetic nervous system activity in brown adipose tissue (BAT), a site that regulates energy expenditure in rodents. A bolus central infusion of urotensin II at a dose of 1 nmol/rat into the third cerebral ventricle decreased food intake (p<0.05). Additionally, urotensin II induced c-Fos-like-immunoreactivity (c-FLI) in the paraventricular nucleus (PVN) as compared with that in the control (phosphate buffered saline [PBS]-treated) group. Furthermore, urotensin II increased BAT UCP 1 mRNA expression (p<0.05). Finally, central infusion of urotensin II significantly increased BAT sympathetic nerve activity, which was accompanied by a significant elevation in BAT temperature (p<0.05) in rats. Taken together, central infusion of urotensin II regulates food intake and BAT sympathetic nerve activity in rats.

Association between type 2 diabetes genetic susceptibility loci and visceral and subcutaneous fat area as determined by computed tomography.

Visceral fat accumulation has an important role in the development of several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of type 2 diabetes have been identified by genome-wide association studies. To examine the association of type 2 diabetes susceptibility loci and visceral fat accumulation, we genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography for measurements of visceral fat area (VFA) and subcutaneous fat area (SFA) for the following single-nucleotide polymorphisms (SNPs): NOTCH2 rs10923931, THADA rs7578597, PPARG rs1801282, ADAMTS9 rs4607103, IGF2BP2 rs1470579, VEGFA rs9472138, JAZF1 rs864745, CDKN2A/CDKN2B rs564398 and rs10811661, HHEX rs1111875 and rs5015480, TCF7L2 rs7901695, KCNQ1 rs2237892, KCNJ11 rs5215 and rs5219, EXT2 rs1113132, rs11037909, and rs3740878, MTNR1B rs10830963, DCD rs1153188, TSPAN8/LGR5 rs7961581, and FTO rs8050136 and rs9939609. None of the above SNPs were significantly associated with VFA. The FTO rs8050136 and rs9939609 risk alleles exhibited significant associations with body mass index (BMI; P=0.00088 and P=0.0010, respectively) and SFA (P=0.00013 and P=0.00017, respectively). No other SNPs were significantly associated with BMI or SFA. Our results suggest that two SNPs in the FTO gene are associated with subcutaneous fat accumulation. The contributions of other SNPs are inconclusive because of a limitation of the sample power.

Apelin-13 microinjection into the paraventricular nucleus increased sympathetic nerve activity innervating brown adipose tissue in rats.

The aim of present study is to clarify the role of apelin in regulating energy homeostasis in brown adipose tissue (BAT). We examined the central effects of apelin-13 on the brain c-fos like immunoreactivity (c-FLI), BAT temperature and the activity of the sympathetic nerve activity innervating BAT in rats. In the hypothalamus, central infusion into the third cerebral ventricle (i3vt) of apelin-13 caused induction of c-FLI in the paraventricular nucleus (PVN) compared with the controls (PBS-treated) group. In addition, microinjection of apelin-13 into the PVN produced significant increases in BAT temperature. Furthermore, microinjection of apelin-13 treatment increased BAT sympathetic nerve activity compared with controls. We conclude that apelin-13 microinjection into PVN increases sympathetic nerve activity innervating BAT.

Effect of peripheral administration of cholecystokinin on food intake in apolipoprotein AIV knockout mice.

Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are satiation factors secreted by the small intestine in response to lipid meals. Apo AIV and CCK-8 has an additive effect to suppress food intake relative to apo AIV or CCK-8 alone. In this study, we determined whether CCK-8 (1, 3, or 5 µg/kg ip) reduces food intake in fasted apo AIV knockout (KO) mice as effectively as in fasted wild-type (WT) mice. Food intake was monitored by the DietMax food system. Apo AIV KO mice had significantly reduced 30-min food intake following all doses of CCK-8, whereas WT mice had reduced food intake only at doses of 3 µg/kg and above. Post hoc analysis revealed that the reduction of 10-min and 30-min food intake elicited by each dose of CCK-8 was significantly larger in the apo AIV KO mice than in the WT mice. Peripheral CCK 1 receptor (CCK1R) gene expression (mRNA) in the duodenum and gallbladder of the fasted apo AIV KO mice was comparable to that in WT mice. In contrast, CCK1R mRNA in nodose ganglia of the apo AIV KO mice was upregulated relative to WT animals. Similarly, upregulated CCK1R gene expression was found in the brain stem of apo AIV KO mice by in situ hybridization. Although it is possible that the increased satiating potency of CCK in apo AIV KO mice is mediated by upregulation of CCK 1R in the nodose ganglia and nucleus tractus solitarius, additional experiments are required to confirm such a mechanism.

Adult-onset Still's disease with macrophage activation syndrome successfully treated with a combination of methotrexate and etanercept.

We report a 16-year-old female case of intractable adult-onset Still's disease accompanied by macrophage activation syndrome, who went into full remission after switching from infliximab to etanercept. Although the disease promptly relapsed when etanercept was discontinued, she again responded fully upon the reintroduction of etanercept. Furthermore, the effect of etanercept was apparently enhanced by combining it with a sufficient dose of methotrexate. This combination therapy should be considered as one of treatment options for the disease.

Spleen-derived interleukin-10 downregulates the severity of high-fat diet-induced non-alcoholic fatty pancreas disease.

Obesity is associated with systemic low-grade inflammation and is a risk factor for non-alcoholic fatty pancreas disease (NAFPD), but the molecular mechanisms of these associations are not clear. Interleukin (IL)-10, a potent anti-inflammatory cytokine, is released during acute pancreatitis and is known to limit inflammatory responses by downregulating the release of proinflammatory mediators. The origin of IL-10 that suppresses pancreatitis has not been investigated. Since obesity is known to reduce expression of proinflammatory cytokines in the spleen, we examined whether spleen-derived IL-10 regulates NAFPD caused by high-fat (HF) diet-induced obesity. The following investigations were performed: 1) IL-10 induction from spleen was examined in male mice fed a HF diet; 2) triglyceride content, expression of pro- and anti-inflammatory cytokines and infiltration of M1 and M2 macrophages were determined to evaluate ectopic fat accumulation and inflammatory responses in the pancreas of splenectomy (SPX)-treated mice fed HF diet; 3) exogenous IL-10 was systemically administered to SPX-treated obese mice and the resulting pathogenesis caused by SPX was assessed; and 4) IL-10 knockout (IL-10KO) mice were treated with SPX and ectopic fat deposition and inflammatory conditions in the pancreas were investigated. Obesity impaired the ability of the spleen to synthesize cytokines, including IL-10. SPX aggravated fat accumulation and inflammatory responses in the pancreas of HF diet-induced obese mice and these effects were inhibited by systemic administration of IL-10. Moreover, SPX had little effect on fat deposition and inflammatory responses in the pancreas of IL-10KO mice. Our findings indicate that obesity reduces IL-10 production by the spleen and that spleen-derived IL-10 may protect against the development of NAFPD.

Intraportal administration of DPP-IV inhibitor regulates insulin secretion and food intake mediated by the hepatic vagal afferent nerve in rats.

Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and suppresses food intake. Recent studies indicate that the hepatic vagal afferent nerve is involved in this response. Dipeptidyl peptidase-IV (DPP-IV) inhibitor extends the half-life of endogenous GLP-1 by preventing its degradation. This study aimed to determine whether DPP-IV inhibitor-induced elevation of portal GLP-1 levels affect insulin secretion and feeding behavior via the vagal afferent nerve and hypothalamus. The effect of DPP-IV inhibitor infusion into the portal vein or peritoneum on portal and peripheral GLP-1 levels, food intake, and plasma insulin and glucose was examined in sham-operated and vagotomized male Sprague-Dawley rats. Analyses of neuronal histamine turnover and immunohistochemistry were used to identify the CNS pathway that mediated the response. Intraportal administration of the DPP-IV inhibitor significantly increased portal (but not peripheral) GLP-1 levels, increased insulin levels, and decreased glucose levels. The DPP-IV inhibitor suppressed 1- and 12- but not 24-h cumulative food intake. Intraportal infusion of the DPP-IV inhibitor increased hypothalamic neuronal histamine turnover and increased c-fos expression in several areas of the brain. These responses were blocked by vagotomy. Our results indicate that DPP-IV inhibitor-induced changes in portal but not systemic GLP-1 levels affect insulin secretion and food intake. Furthermore, our findings suggest that a neuronal pathway that includes the hepatic vagal afferent nerve and hypothalamic neuronal histamine plays an important role in the pharmacological actions of DPP-IV inhibitor.

Intraperitoneal administration attenuates thiazolidinedione-induced hepatic steatosis in KKAy mice with increased hepatic peroxisome proliferator-activated receptor (PPAR)γ mRNA expression.

BACKGROUND: The pathogenesis of thiazolidinediones (TZDs)-induced hepatic steatosis in genetically obese diabetic mice has not been fully clarified. We herein examined the effects of pioglitazone treatment on liver histology. METHODS: To investigate TZDs-induced hepatic steatosis, KKAy mice were treated with pioglitazone orally or by intraperitoneal injection. RESULTS: Orally administered pioglitazone at 15 and/or 50 mg/kg/day worsened the hepatic steatosis in KKAy mice, however, the treatment at 50 mg/kg/day was not worse than that at 15 mg/kg/day. The basal expression of peroxisome proliferator-activated receptor (Ppar)γ mRNA in the liver was upregulated to approximately 10% of that in white adipose tissue in these mice. Although no induction of hepatic Pparg mRNA by pioglitazone treatment was observed, the mRNA expression of the downstream lipogenic enzymes significantly increased. On the other hand, intraperitoneal administration of 15 mg/kg/day did not lead to deterioration of the hepatic steatosis of KKAy mice. Moreover, intraperitoneal administration led to an accompanying shift of fat distribution from intra-abdominal to subcutaneous adipose depots, and further increases in the serum adiponectin levels. In addition, a 5 day treatment without any change in body weight led to an obvious improvement in hepatic steatosis. CONCLUSIONS: Intraperitoneal administration of pioglitazone can act more strongly on intra-abdominal adipose tissues, and attenuates TZDs-induced hepatic steatosis in KKAy mice. The present study suggests that hepatic steatosis due to chronic treatment with TZDs is affected by the balance between endogenous lipogenesis in the liver and the lipid storage in adipose tissues, both occurring through PPARγ.