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Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic triglycerides (TG) and hyperglycemia arising due to persistent insulin resistance, and is profoundly linked to obesity. However, there is currently no established treatment for NAFLD in obese human subjects. We previously isolated Helz2, the expression of which was upregulated in human and mouse NAFLD, and its deletion activated the hepatic expression of functional leptin receptor long form (Leprb) and suppressed NAFLD development and body weight (BW) gain in obese mice. A high-throughput assay of small-molecule drugs revealed that guanabenz acetate (Ga), originally used to treat hypertension, possesses a high affinity constant against HELZ2, and its administration activates LEPRB expression in HepG2 cells in vitro. The chronic oral administration of Ga shows the selective leptin sensitization in the liver via upregulation of hepatic Leprb expression, which affects expression of genes involved in lipogenesis and fatty acid β-oxidation and diminishes hepatocyte hypertrophy with droplets enriched in TG in high-fat diet-induced obese mice. This activity significantly improves insulin resistance to decrease hyperglycemia and hepatocyte and adipocyte weights, resulting in BW reduction without reducing food intake. Regarding drug repositioning, Ga has the potential to effectively treat NAFLD and hyperglycemia in obese patients.

Aim: To investigate the mechanism and in vivo effects of MK-0626, a dipeptidyl peptidase-4 inhibitor, on hepatic steatosis using ob/ob mice., Methods: We analyzed obese (ob/ob) 8-wk-old male mice that had been randomly divided into two groups of ob/ob mice (n = 16 each) and were treated with 1.5 or 3 mg/kg MK-0626 and two control groups of untreated ob/ob mice and lean littermates (n = 16 each). All mice were fed a normal chow diet with or without MK-0626 for either four or eight weeks. Blood samples were collected, and total hepatectomy was performed., Results: The administration of dietary MK-0626 ameliorated the hepatic lipid accumulation in ob/ob mice treated with 3 mg/kg MK-0626 (3 MK), P < 0.05, vs untreated ob/ob mice (ob/ob). The MK-0626 treatment reduced the serum alanine aminotransferase levels (both treatment groups, P < 0.05 vs ob/ob) and glucoses/insulin levels/calculated HOMA scores (1.5 MK, P < 0.05 vs ob/ob; 3 MK, P < 0.01 vs ob/ob) and increased the serum adiponectin levels (3 MK, P < 0.05 vs ob/ob) in a dose-dependent manner. The MK-0626 treatment increased the mRNA expression of peroxisome proliferator-activated receptor α/microsomal triglyceride transfer protein (1.5 MK, P < 0.05 vs ob/ob; 3 MK, P < 0.01 vs ob/ob) but reduced the sterol regulatory element binding transcription factor-1c/fatty acid synthase/stearoyl-CoA desaturase-1 (both treatment groups, P < 0.01 vs ob/ob). The MK-0626 treatment increased the activity of AMP-activated protein kinase (AMPK) (both treatment groups, P < 0.01 vs ob/ob)., Conclusion: MK-0626 could attenuate hepatic steatosis through enhancing AMPK activity, inhibiting hepatic lipogenic gene expression, enhancing triglyceride secretion from liver and increasing serum adiponectin levels.

Obesity arises from impaired energy balance, which is centrally coordinated by leptin through activation of the long form of leptin receptor (Leprb). Obesity causes central leptin resistance. However, whether enhanced peripheral leptin sensitivity could overcome central leptin resistance remains obscure. A peripheral metabolic organ targeted by leptin is the liver, with low Leprb expression. We here show that mice fed a high-fat diet (HFD) and obese patients with hepatosteatosis exhibit increased expression of hepatic helicase with zinc finger 2, a transcriptional coactivator (Helz2), which functions as a transcriptional coregulator of several nuclear receptors, including peroxisome proliferator-activated receptor γ in vitro. To explore the physiological importance of Helz2, we generated Helz2-deficient mice and analyzed their metabolic phenotypes. Helz2-deficient mice showing hyperleptinemia associated with central leptin resistance were protected against HFD-induced obesity and had significantly up-regulated hepatic Leprb expression. Helz2 deficiency and adenovirus-mediated liver-specific exogenous Leprb overexpression in wild-type mice significantly stimulated hepatic AMP-activated protein kinase on HFD, whereas Helz2-deficient db/db mice lacking functional Leprb did not. Fatty acid-β oxidation was increased in Helz2-deficeint hepatocytes, and Helz2-deficient mice revealed increased oxygen consumption and decreased respiratory quotient in calorimetry analyses. The enhanced hepatic AMP-activated protein kinase energy-sensing pathway in Helz2-deficient mice ameliorated hyperlipidemia, hepatosteatosis, and insulin resistance by reducing lipogenic gene expression and stimulating lipid-burning gene expression in the liver. These findings together demonstrate that Helz2 deficiency ameliorates HFD-induced metabolic abnormalities by stimulating endogenous hepatic Leprb expression, despite central leptin resistance. Hepatic HELZ2 might be a novel target molecule for the treatment of obesity with hepatosteatosis.

We discovered a new anorexigenic protein, nesfatin/nucleobindin-2 (NUCB2), which includes an EF-hand, calcium-binding motif. Nesfatin/NUCB2 is converted to nesfatin-1, which may be a physiologically active form in the body. Centrally and systemically administered nesfatin-1 inhibits appetite and body weight gain in rodents. The mid-segment of nesfatin-1 appears to be important in the inhibition of food intake. Intranasal administration of the mid-segment inhibits appetite. Nesfatin-1 may also be involved in the regulation of gastrointestinal function and insulin secretion. We have summarized the recent progress in the research of nesfatin-1.

The patient was a 69-year-old woman with a family history of type 2 diabetes. Her body mass index was 31.5. She was diagnosed as type 2 diabetes 32 years previously, and treated with insulin for 8 years. She had no episode of weight loss. She was hospitalized with diabetic ketoacidosis for the first time. Her GAD antibodies were not detected. However, ICA antibodies and insulin antibodies were positively detected. She was diagnosed with type 1 diabetes. Interestingly, her diabetes state was controlled to the same level after recovery from ketoacidosis.

Menopause is one of the triggers that induce obesity. Estradiol (E2), corticotropin-releasing hormone (CRH), and hypothalamic neuronal histamine are anorexigenic substances within the hypothalamus. This study examined the interactions among E2, CRH, and histamine during the regulation of feeding behavior and obesity in rodents. Food intake was measured in rats after the treatment of E2, alpha-fluoromethyl histidine, a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine, or CRH antagonist. We measured food intake and body weight in wild-type mice or mice with targeted disruption of the histamine receptors (H1-R) knockout (H1KO mice). Furthermore, we investigated CRH content and histamine turnover in the hypothalamus after the E2 treatment or ovariectomy (OVX). We used immunohistochemical staining for estrogen receptors (ERs) in the histamine neurons. The E2-induced suppression of feeding was partially attenuated in rats pre-treated with alpha-fluoromethyl histidine or CRH antagonist and in H1KO mice. E2 treatment increased CRH content and histamine turnover in the hypothalamus. OVX increased food intake and body weight, and decreased CRH content and histamine turnover in the hypothalamus. In addition, E2 replacement reversed the OVX-induced changes in food intake and body weight in wild-type mice but not in H1KO mice. Immunohistochemical analysis revealed ERs were expressed on histamine neurons and western blotting analysis and pre-absorption study confirmed the specificity of ER antiserum we used. These results indicate that CRH and hypothalamic neuronal histamine mediate the suppressive effects of E2 on feeding behavior and body weight.

Obesity is a heterogeneous syndrome. The pathophysiology of obesity seems to be simple because of a chronic excess of nutrient intake relative to the low level of energy expenditure. However, several pathogenic processes are involved in the development of obesity. Moreover, there are primary diseases that cause secondary obesity, also called symptomatic obesity, in process of those clinical explorations. The symptomatic obesity is classified as endocrine, central nervous-related, congenital and drug-induced obesity. Since simple obesity is diagnosed after excluding symptomatic obesity, we should understand pathophysiology and clinical characteristics of each of primary diseases that cause obesity.

Goals: To investigate whether there is a relationship between hiatus hernia (HH) and kyphosis or obesity in elderly Japanese persons., Background: The causes of HH in the elderly are unclear., Study: We enrolled 147 consecutive patients aged over 50 years in this study. Endoscopic assessment of the size of HH was performed by using a modified Makuuchi classification with grades from 1 (no HH) to 4 (>3 cm). The gastroesophageal flap valve (GEFV) was also graded from I to IV. Kyphosis was evaluated from a lateral photograph by measuring the modified Cobb angle (CA) and calculating the kyphosis index (KI). Body mass index (BMI) was used to evaluate obesity., Results: In women, there were significant differences of both the CA (analysis of variance, P<0.0001) and KI (Kruskal-Wallis test, P<0.01) between each grade of HH. Differences of the CA (P<0.001) and KI (P<0.001) were also seen between the grades of GEFV. None of these differences were detected in men. In women, the CA (r=0.556, P<0.0001) and KI (P<0.0001) were positively correlated with age, but this was not so in men. Neither sex showed an association between BMI and the grade of either HH or GEFV. However, there was a weak negative correlation between age and BMI in women (r=-0.223, P<0.05) and men (r=-0.334, P<0.05)., Conclusions: The size of HH is associated with the severity of kyphosis, not with obesity, in elderly Japanese women. Age is a risk factor for both kyphosis and HH.

Objective: CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP)-10/growth arrest and DNA damage 153 is a dominant-negative member of the C/EBP transcription family and inhibits adipogenesis in vitro. The study was undertaken to determine the role of CHOP in obesity in vivo., Research Methods and Procedures: Changes in daily food consumption and body weight were measured. The weight of white and brown adipose tissue was compared between Chop(+/+) and (-/-) mice fed normal chow or a high-fat diet. Glucose and insulin tolerance tests were done, and serum adipocytokine was measured to determine their metabolic state. Fat cell size of subcutaneous and mesenteric adipose tissue was microscopically observed. C/EBP expression in white adipose tissue was examined by Western blot., Results: Female Chop(-/-) mice had significantly greater body weight and adiposity than Chop(+/+) mice, although daily food intake and rectal temperature did not differ. In comparison with Chop(+/+) mice, glucose tolerance and insulin sensitivity did not differ in female Chop(-/-) mice, but levels of plasma leptin and adiponectin were higher. High-fat diet feeding resulted in obesity in female Chop(+/-) and (-/-) mice, although caloric intake did not differ from that of Chop(+/+) mice. Fat cell area was larger in mesenteric fat but not in subcutaneous fat in Chop(-/-) mice fed a high-fat diet. C/EBPbeta and the 30-kDa form of C/EBPalpha expressions were increased in parametrial fat of Chop(-/-) mice, but the 42-kDa form of C/EBPalpha expression was lower than in Chop(+/+) mice., Discussion: CHOP deficiency causes obesity in female animals without severe metabolic disorders, and C/EBP's expression may be considered to participate in the process.

Withdrawal of estrogen by ovariectomy increases adiposity, but decreases the circulating levels of the ob gene product, leptin, which inhibits food intake. The reduction of circulating leptin levels may thus play an important role in the induction of obesity by ovariectomy. To examine this hypothesis, body weight change by ovariectomy was investigated in leptin-deficient genetically obese (ob/ob) mice with leptin supplement. Prior to the operation, obese (ob/ob) female mice were treated with intraperitoneal administration of recombinant mouse leptin (1.0 microg/g body weight/day) for 8 days. Then, half of the leptin-treated mice and their lean littermates were bilaterally ovariectomized and their body weight changes were observed for 56 days. From 16 days after the operation, a significant increase in body weight by ovariectomy was observed only in lean mice without leptin treatment. From 44 days, a significant body weight gain by ovariectomy was observed in leptin-treated obese mice. Ovariectomy significantly increased retroperitoneal white adipose tissue weight in their lean littermates, but not in leptin-treated obese mice. It was suggested that the reduction of circulating leptin levels may play an important role in the increases of acute phase body weight gain by ovariectomy, but during static phase, the direct effects of estrogen withdrawal may appear independent of leptin-mediated effects.

Concentrations of the soluble leptin receptor (sOB-R) may be related to leptin resistance in obesity. We measured sOB-R concentrations in serum in 103 non-diabetic Japanese men and women. All subjects were grouped according to body mass index (BMI; in kg/m(2)). Serum sOB-R concentrations did not differ significantly between normal-weight (18.5 < or = BMI < 25.0) men and women, but were significantly higher in underweight subjects (BMI < 18.5) than in normal-weight subjects. In contrast, overweight (25 < or = BMI < 30) and obese (30 < or = BMI < 35.0, 35.0 < or = BMI < 40, and BMI > or = 40) subjects had significantly lower sOB-R concentrations than did normal-weight subjects. Serum sOB-R concentrations were inversely correlated with BMI and serum immunoreactive leptin concentrations. Very low-energy diet therapy for 4 wk significantly lowered serum immunoreactive leptin concentrations but did not significantly affect serum sOB-R concentrations. Serum sOB-R concentrations did not change significantly during the menstrual cycle. Our results showed that serum sOB-R concentrations decrease with increasing BMI and that sex hormones likely do not affect serum sOB-R concentrations in non-pregnant women. The reduction in serum sOB-R concentrations in overweight and obese persons may reflect downregulation of hypothalamic leptin receptor production as a result of an increase in circulating leptin and might be an important factor in leptin resistance.

Nesfatin-1 acts on the hypothalamus and regulates the autonomic nervous system. However, the hypothalamic mechanisms of nesfatin-1 on the autonomic nervous system are not well understood. In this study, we found that intracerebroventricular (ICV) administration of nesfatin-1 increased the extracellular signal-regulated kinase (ERK) activity in rats. Furthermore, the activity of sympathetic nerves, in the kidneys, liver, and white adipose tissue (WAT), and blood pressure was stimulated by the ICV injection of nesfatin-1, and these effects were abolished owing to pharmacological inhibition of ERK. Renal sympathoexcitatory and hypertensive effects were also observed with nesfatin-1 microinjection into the paraventricular hypothalamic nucleus (PVN). Moreover, nesfatin-1 increased the number of phospho (p)-ERK1/2-positive neurons in the PVN and coexpression of the protein in neurons expressing corticotropin-releasing hormone (CRH). Pharmacological blockade of CRH signaling inhibited renal sympathetic and hypertensive responses to nesfatin-1. Finally, sympathetic stimulation of WAT and increased p-ERK1/2 levels in response to nesfatin-1 were preserved in obese animals such as rats that were fed a high-fat diet and leptin receptor-deficient Zucker fatty rats. These findings indicate that nesfatin-1 regulates the autonomic nervous system through ERK signaling in PVN-CRH neurons to maintain cardiovascular function and that the antiobesity effect of nesfatin-1 is mediated by hypothalamic ERK-dependent sympathoexcitation in obese animals. [ABSTRACT FROM AUTHOR]

Background We recently identified a novel anorexigenic protein, nesfatin-1, which is processed from nesfatin/nucleobindin-2 (NUCB2). However, the clinical importance of this protein has not been determined. Objective To investigate its clinical significance in humans, we have established a new specific enzyme-linked immunosorbent assay (ELISA) for human nesfatin-1 in peripheral blood and measured its circulating concentration in healthy subjects. Design The new sandwich-type ELISA method was validated and then used to measure nesfatin-1 levels in plasma samples, under overnight fasting conditions, followed by oral glucose tolerance and meal tests. Patients and measurements A total of 43 nonobese males (age: 24·5 ± 0·6 , body mass index (BMI); 21·1 ± 0·3 kg/m2) were recruited to the study for evaluating fasting concentrations of nesfatin-1. In those, fifteen subjects underwent a 75- g oral glucose tolerance test (OGTT) and another 15 underwent a meal test. In addition, fasting concentrations of nesfatin-1 were measured in nine males with high BMI (age: 32·4 ± 3·7 , BMI; 37·3 ± 3·8 kg/m2). Results Peripheral concentrations of nesfatin-1 showed a significant negative correlation with BMI, percentage body fat, body fat weight and blood glucose ( P < 0·05). Nesfatin-1 concentrations were not significantly changed during OGTT and meal tests. Fasting nesfatin-1 levels were significantly lower in subjects with high BMI compared to nonobese subjects ( P < 0·05). Conclusions A new specific and sensitive ELISA for nesfatin-1 was established. Further accumulation of clinical observations is necessary to clarify the role of circulating nesfatin-1 in various metabolic disorders. [ABSTRACT FROM AUTHOR]

Background. The number of patients with morbid obesity is increasing worldwide. However, the prevalence of morbid obesity is still low in Japan, and therefore few systematic investigations of liver dysfunction in this population have so far been carried out. This study aimed to investigate the clinical characteristics in severe obese Japanese patients undergoing laparoscopic Roux-en-Y gastric bypass surgery (LRYGB). Methods. Eighty-four patients with severe obesity, including 61 Japanese and 23 non-Japanese patients, were analyzed. Results. The mean body mass index (BMI) was 43.7 ± 7.8 kg/m2, and there was no difference between Japanese and non-Japanese patients. Nonalcoholic fatty liver disease (NAFLD) was observed in 45/59 (76.2%) of the Japanese patients. Although there were no differences in the BMI and body weight, serum ALT was higher in Japanese patients in comparison to non-Japanese patients ( P < 0.05). The indices for insulin resistance were significantly higher in the Japanese patients in comparison to non-Japanese patients ( P < 0.01). The liver/spleen computed tomography (CT) ratios were lower in Japanese patients ( P < 0.05). The laboratory data and BMI significantly improved at 1 year after LRYGB in both groups. Conclusions. Racial difference may exist difference may exist in NAFLD in patients with severe obesity. When the BMI is similar, liver dysfunction among Japanese patients with severe obesity tends to be higher than in non-Japanese patients. Japanese patients with severe obesity must therefore reduce their body weight to a greater degree in comparison to non-Japanese patients with the same BMI. LRYGB can achieve effective weight control and lower ALT levels in Japanese patients with severe obesity. [ABSTRACT FROM AUTHOR]

Summary: Mazindol, a centrally acting monoamine re-uptake inhibitor, enhances satiety and supports body weight loss, but response to this drug among obese patients is very variable. The possible involvement of the Trp64Arg polymorphism of the β3-adrenergic receptor (ADRB3) gene in the development of severe obesity and weight loss response to anorexigenic drugs has not been established. In the present study, the allelic frequency of the Trp64Arg ADRB3 gene polymorphism was determined in massively obese Japanese outpatients (BMI>35kg/m2), and we investigated whether allelic differences may determine the weight loss effect of mazindol. The allelic frequency of Trp64Arg heterozygotes and homozygotes did not differ in severely obese subjects compared to non-obese subjects. Trp64Arg heterozygotes experienced significantly increased weight loss and reduced blood pressure following mazindol administration for 12 weeks. Thus the ADRB3 gene polymorphism is predictive for difficulty in weight reduction with mazindol treatment, but is not related to the development of severe obesity in the Japanese population. [Copyright &y& Elsevier]

Highlights: [•] PVN NUCB2/nesfatin-1 expression rises in early light phase, exhibiting diurnal rhythm. [•] NUCB2/nesfatin-1 rise restricts light phase feeding, contributing to feeding rhythm. [•] PVN-specific shRNA-driven knockdown of NUCB2 mRNA expression elevates food intake. [•] Obese rats show impaired NUCB2/nesfatin-1 rise, arrhythmic feeding and hyperphagia. [•] Nesfatin-1 injection ameliorates arrhythmic feeding and hyperphagia in obese rats. [ABSTRACT FROM AUTHOR]

Abstract: Nesfatin-1, an anorexigenic protein, is ubiquitously expressed in the body. However, the exact mechanism underlying the in vivo regulation of production of nesfatin/nucleobindin-2 (NUCB2), a precursor protein of nesfatin-1, is unknown. We investigated the influence of modulation of autonomic nerve activity by a ventromedial hypothalamus (VMH) lesion and the subsequent effect on nesfatin/NUCB2 production in rat tissues innervated by the peripheral nervous system. Nesfatin/NUCB2 is strongly expressed in the pancreas and liver, moderately expressed in subcutaneous and visceral fat tissues and interscapular brown adipose tissue (iBAT), but is weakly expressed in the skeletal muscles. Our study results showed that the VMH lesion in VMH-lesioned rats did not affect nesfatin/NUCB2 expression in the pancreas, liver, skeletal muscle, and iBAT; however, the protein expression was significantly high in both subcutaneous and visceral fat tissues. In addition, continuous peripheral administration of carbachol for 5 days did not affect nesfatin/NUCB2 expression, but chemical sympathectomy using 6-hydroxydopamine mimicked the effect of VMH lesion by showing significantly high nesfatin/NUCB2 expression in the subcutaneous fat tissues. These results show that VMH lesion can modulate the autonomic nervous system activity and balance and increase nesfatin/NUCB2 expression in white adipose tissues of rats. Further, this action may be mediated via inhibition of the sympathetic nerve activity. [Copyright &y& Elsevier]

Abstract: An anorexigenic peptide, nesfatin-1 was found in rat hypothalamus, and its expression in the paraventricular nucleus of the hypothalamus was reduced by starvation. Intracerebroventricular administration dose-dependently inhibited food intake for 6h in male Wistar and leptin resistant, Zucker fatty rats. There may be a crosstalk between nesfatin-1 pathway and melanocortin pathway in the brain. Nesfatin-1 neurons co-express with oxytocin, vasopressin and melanin concentrating hormone in the hypothalamus. Intraperitoneal administration of nesfatin-1 and its mid-segment dose-dependently inhibited food intake for 3h. Mid-segment of nesfatin-1 decreased food intake under leptin-resistant animal models of obesity. Intraperitoneal administration of the mid-segment of nesfatin-1 increased proopiomelanocortin and cocain- and amphetamine-related peptide mRNA expression in the nucleus of the solitary tract, but not in arcuate nucleus of the hypothalamus. In this review, we summarized recent progress in the research about the possible mechanism of nesfatin-1-induced anorexia. [Copyright &y& Elsevier]

• NUCB2/nesfatin-1 is regulated by nutritional state. • NUCB2/nesfatin1 plays a physiological role to reduce food intake in multiple species. • Systemic and central administration of NUCB2/nesfatin-1 improve glucose metabolism. • NUCB2/nesfatin-1 stimulates fat utilization and inhibits lipogenesis and lipid accumulation. Since its discovery in 2006 by Oh-I and colleagues, NUCB2/nesfatin-1 encoded by nucleobindin-2 (NUCB2) has drawn sustained attention as reflected in over 500 publications. Among those, more than half focused on the alterations of food intake, body weight and metabolism (glucose, fat) induced by nesfatin-1 and/or NUCB2/nesfatin-1. In the current review we discuss the existing literature focusing on NUCB2/nesfatin-1's influence on food intake, body weight and glucose as well as fat metabolism and highlight gaps in knowledge. [ABSTRACT FROM AUTHOR]