Haruka Amitani

Plasma obestatin concentrations are negatively correlated with body mass index, insulin resistance index, and plasma leptin concentrations in obesity and anorexia nervosa.

BACKGROUND Obestatin is a recently identified ghrelin gene product that was reported to inhibit appetite and gastric motility in contrast to ghrelin. We investigated fasting obestatin and ghrelin levels in patients with obesity and anorexia nervosa. METHODS Fasting plasma obestatin, acyl-ghrelin, desacyl-ghrelin, leptin, glucose serum adiponectin, and insulin were measured in 10 obese subjects, 11 restricting-type anorexics, and 11 control subjects. RESULTS Obese group had significantly lower levels of obestatin (p < .01), while anorexic group had significantly higher levels (p < .01). Obestatin was negatively correlated with body mass index (BMI) (r = -.74), glucose (r = -.56), insulin (r = -.55), leptin (r = -.66), and also with the homeostasis model assessment of insulin resistance (HOMA-R) (r = -.49) and was positively correlated with acyl-ghrelin (r = .65) and desacyl-ghrelin (r = .60). No correlation was seen between obestatin and adiponectin, but the latter was negatively correlated with both acyl-ghrelin and desacyl-ghrelin. Desacyl-ghrelin to acyl-ghrelin ratio was significantly different between anorexic and control groups (p < .05), while no difference was seen between obese and control groups. CONCLUSIONS Both obestatin and ghrelin are increased in anorexic and decreased in obesity. We suggest that obestatin is a nutritional marker reflecting body adiposity and insulin resistance.

Cancer cachexia—pathophysiology and management

About half of all cancer patients show a syndrome of cachexia, characterized by anorexia and loss of adipose tissue and skeletal muscle mass. Cachexia can have a profound impact on quality of life, symptom burden, and a patient’s sense of dignity. It is a very serious complication, as weight loss during cancer treatment is associated with more chemotherapy-related side effects, fewer completed cycles of chemotherapy, and decreased survival rates. Numerous cytokines have been postulated to play a role in the etiology of cancer cachexia. Cytokines can elicit effects that mimic leptin signaling and suppress orexigenic ghrelin and neuropeptide Y (NPY) signaling, inducing sustained anorexia and cachexia not accompanied by the usual compensatory response. Furthermore, cytokines have been implicated in the induction of cancer-related muscle wasting. Cytokine-induced skeletal muscle wasting is probably a multifactorial process, which involves a protein synthesis inhibition, an increase in protein degradation, or a combination of both. The best treatment of the cachectic syndrome is a multifactorial approach. Many drugs including appetite stimulants, thalidomide, cytokine inhibitors, steroids, nonsteroidal anti-inflammatory drugs, branched-chain amino acids, eicosapentaenoic acid, and antiserotoninergic drugs have been proposed and used in clinical trials, while others are still under investigation using experimental animals. There is a growing awareness of the positive impact of supportive care measures and development of promising novel pharmaceutical agents for cachexia. While there has been great progress in understanding the underlying biological mechanisms of cachexia, health care providers must also recognize the psychosocial and biomedical impact cachexia can have.

Selective Serotonin Reuptake Inhibitors Modify Physiological Gastrointestinal Motor Activities via 5-HT2c Receptor and Acyl Ghrelin

BACKGROUND Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat anxiety and depressive disorders. These agents may cause upper gastrointestinal (GI) symptoms that lead to their discontinuation. We examined whether SSRIs modify physiologic GI motor activities in freely moving rats. METHODS The SSRIs fenfluramine, fluvoxamine, paroxetine, and fluoxetine were administered to 24-hour food-deprived rats, and then GI motility was measured in conscious, freely moving rats using a strain gauge force transducer method. Plasma acyl ghrelin levels were determined by enzyme immunoassay. RESULTS Plasma acyl ghrelin levels were analyzed in conjunction with fasted motor activities. Acyl ghrelin was increased in association with the occurrence of Phase III-like contractions of the migrating motor complex in the antrum and duodenum. SSRIs decreased acyl ghrelin and changed Phase III-like contractions to fed-like motor activities. Both effects were blocked by 5-HT2c, but not 5-HT1b, receptor antagonist. Neither melanocortin 4 nor the 3/4 receptor antagonists blocked this motor effect, although they restored the anorexia induced by SSRIs. The improving effect on GI motility by 5-HT2c receptor (5-HT2cR) antagonist disappeared after treatment with a growth-hormone secretagogue receptor antagonist, whereas ghrelin or ghrelin-releasing drug such as TJ-43 changed SSRI-induced fed-like motor activities to fasted activities. CONCLUSIONS SSRIs have inhibitory effects on acyl ghrelin and GI motor activities through 5-HT2cR. Our study identifies the importance and divergence of central 5-HT2cR pathways that regulate GI motor activities through ghrelin and feeding/energy metabolism via melanocortin 4 receptor signaling.

Obestatin, Acyl Ghrelin, and Des-acyl Ghrelin Responses to an Oral Glucose Tolerance Test in the Restricting Type of Anorexia Nervosa

BACKGROUND Obestatin is a recently identified peptide encoded by the same ghrelin gene. It has been reported that obestatin has anorexigenic and antigastroprokinetic activities as opposed to ghrelin. We investigated simultaneously obestatin, acyl ghrelin, and des-acyl ghrelin in the restricting type of anorexia nervosa (AN-R) patients. METHODS Three hormonal responses to the oral glucose tolerance test (OGTT) were measured in 10 AN-R patients and 10 healthy women. RESULTS Plasma obestatin, acyl ghrelin, and des-acyl ghrelin levels were significantly higher in AN-R patients than in control subjects throughout the OGTT. All of the three hormones decreased after the OGTT in both groups. CONCLUSIONS We found that AN-R patients exhibited increased plasma levels of obestatin, acyl ghrelin, and des-acyl ghrelin throughout the OGTT compared with control subjects. The hormonal differences between groups are statistically most significant in obestatin, suggesting obestatin may serve as a marker reflecting both acute and chronic changes of the nutritional state in AN-R patients.

Plasma nesfatin-1 concentrations in restricting-type anorexia nervosa

Restricting-type anorexia nervosa (AN-R) is characterized by chronic food restriction and severe emaciation due to various cognitive biases such as a distorted self-image. In spite of several treatments, AN-R continues to be a refractory disease because of its unknown pathogenesis. Although previous studies have shown that changes in feeding regulatory peptides such as ghrelin are involved in anorexia, few reports have described the relationship between AN-R and nesfatin-1, a recently identified satiety peptide. Therefore, we examined the plasma nesfatin-1 levels in AN-R patients to determine its role in AN-R. A total of 15 women participated in the study; 7 patients with AN-R and 8 age-matched healthy controls (average BMI, 13.02 ± 0.30 vs. 21.57 ± 0.48, respectively). Our results showed that plasma nesfatin-1 levels were significantly lower in AN-R group than in control group (6.23 ± 0.70 ng/ml vs. 8.91 ± 0.85 ng/ml, respectively, P<0.05). Plasma acyl ghrelin and des-acyl ghrelin levels were significantly higher in AN-R group than in control group (acyl ghrelin: 62.4 ± 10.15 fmol/ml vs. 27.20 ± 5.60 fmol/ml, P<0.01 and des-acyl ghrelin: 300.17 ± 55.95 fmol/ml vs. 107.34 ± 40.63 fmol/ml, P<0.05). Although AN-R is associated with emaciation for a prolonged period, our result suggested that nesfatin-1 levels may be regulated by nutrition status and response to starvation.

Anti-ghrelin immunoglobulins modulate ghrelin stability and its orexigenic effect in obese mice and humans.

Obese individuals often have increased appetite despite normal plasma levels of the main orexigenic hormone ghrelin. Here we show that ghrelin degradation in the plasma is inhibited by ghrelin-reactive IgG immunoglobulins, which display increased binding affinity to ghrelin in obese patients and mice. Co-administration of ghrelin together with IgG from obese individuals, but not with IgG from anorectic or control patients, increases food intake in rats. Similarly, chronic injections of ghrelin together with IgG from ob/ob mice increase food intake, meal frequency and total lean body mass of mice. These data reveal that in both obese humans and mice, IgG with increased affinity for ghrelin enhances ghrelin’s orexigenic effect, which may contribute to increased appetite and overeating.

The role of leptin in the control of insulin-glucose axis

Obesity and diabetes mellitus are great public health concerns throughout the world because of their increasing incidence and prevalence. Leptin, the adipocyte hormone, is well known for its role in the regulation of food intake and energy expenditure. In addition to the regulation of appetite and satiety that recently has attracted much attentions, insight has also been gained into the critical role of leptin in the control of the insulin-glucose axis, peripheral glucose and insulin responsiveness. Since the discovery of leptin, leptin has been taken for its therapeutic potential to obesity and diabetes. Recently, the therapeutic effects of central leptin gene therapy have been reported in insulin-deficient diabetes in obesity animal models such as ob/ob mise, diet-induced obese mice, and insulin-deficient type 1 diabetes mice, and also in patients with inactivating mutations in the leptin gene. Herein, we review the role of leptin in regulating feeding behavior and glucose metabolism and also the therapeutic potential of leptin in obesity and diabetes mellitus.

Central leptin gene therapy, a substitute for insulin therapy to ameliorate hyperglycemia and hyperphagia, and promote survival in insulin-deficient diabetic mice

Long-term benefits of central leptin gene therapy in insulin-deficient diabetes are not known despite its therapeutic effects in obesity animal models such as ob/ob and diet-induced obese mice. Adult male mice were injected intraperitoneally with streptozotocin (STZ, 200mg/kg) to induce insulitis. A week later, only diabetic STZ-pretreated mice (blood glucose >350 mg/dl) received intracerebroventricularly (icv) an injection of recombinant adeno-associated virus vector (rAAV) encoding either green fluorescent protein (control), or leptin gene (rAAV-lep). Body weight (BW), food intake, blood glucose, insulin and survival rate responses were monitored post-icv injection at regular intervals for 52 weeks. The STZ pre-injected diabetic mice remained hyperphagic, gradually lost BW and died by week 6 after receiving control vector. In marked contrast, injection of rAAV-lep to raise hypothalamic leptin levels, rescued the STZ-pretreated mice from early mortality, gradually curbed hyperphagia to normalize intake by week 20, and maintained BW at significantly lower than the control range. Blood glucose levels in these mice started to recede dramatically by week 2-3 to normalize by week 8, and euglycemia was sustained during the remaining course of the experiment. rAAV-lep injected mice did not exhibit any discernible untoward gross behavioral changes and diabetic complications and showed a partial return of pancreatic beta-cell function. These results show for the first time that one time central leptin gene therapy is effective and durable in reinstating euglycemia and energy homeostasis for extended periods in the absence of insulin.

Comparison of the anorexigenic activity of CRF family peptides.

Corticotropin releasing factor (CRF) family peptides have an important role in the control of food intake. We investigated the effects of CRF family peptides on food intake and body weight gain in mice. Of the CRF family peptides, including CRF, urocortin1 (Ucn1), urocortin2 (Ucn2) and urocortin3 (Ucn3), peripherally administered Ucn1 was shown to have the most potent inhibitory effect on the food intake and body weight gain of both lean and high fat fed obese mice. In addition, repeated administration of Ucn1 lowered blood glucose and acylated ghrelin, and decreased the visceral fat weight of high fat fed obese mice.

Zinc as an Appetite Stimulator - The Possible Role of Zinc in the Progression of Diseases Such as Cachexia and Sarcopenia

Zinc is required by humans and animals for many physiological functions, such as growth, immune function, and reproduction. Zinc deficiency induces a number of physiological problems, including anorexia, growth retardation, dermatitis, taste disorder, and hypogonadism. Although it is clear that zinc deficiency produces specific and profound anorexia in experimental animals, the connection between zinc deficiency and anorexia is less certain. We were the first to show that orally, but not intraperitoneally, administered zinc rapidly stimulates food intake through orexigenic peptides coupled to the afferent vagus nerve using rats during early-stage zinc deficiency without decreased zinc concentrations in plasma and tissues. We confirmed that a zinc-sufficient diet containing zinc chloride acutely stimulated food intake after short-term zinc deprivation. We also found that orally administered zinc sulfate increased the expression of NPY and orexin mRNA after administration. Using vagotomized rats, we tested whether the increase in food intake after oral administration of zinc was mediated by the vagus nerve. In sham-operated rats, the oral administration of zinc stimulated food intake, whereas zinc and saline administrations did not exhibit differing effects in vagotomized rats. We conclude that zinc stimulates food intake in short-term zinc-deficient rats through the afferent vagus nerve with subsequent effects on hypothalamic peptides associated with food intake regulation. In this review, we describe recent research investigating the roles of zinc as an appetite stimulator in food intake regulation, along with research about hypothalamus, ghrelin, leptin and zinc receptor, and clinical application about anorexia nervosa, cachexia and sarcopenia. The article also presents some promising patents on zinc.