Nicholas T. Bello

Inositol Pyrophosphates Inhibit Akt Signaling, Thereby Regulating Insulin Sensitivity and Weight Gain

The inositol pyrophosphate IP7 (5-diphosphoinositolpentakisphosphate), formed by a family of three inositol hexakisphosphate kinases (IP6Ks), modulates diverse cellular activities. We now report that IP7 is a physiologic inhibitor of Akt, a serine/threonine kinase that regulates glucose homeostasis and protein translation, respectively, via the GSK3β and mTOR pathways. Thus, Akt and mTOR signaling are dramatically augmented and GSK3β signaling reduced in skeletal muscle, white adipose tissue, and liver of mice with targeted deletion of IP6K1. IP7 affects this pathway by potently inhibiting the PDK1 phosphorylation of Akt, preventing its activation and thereby affecting insulin signaling. IP6K1 knockout mice manifest insulin sensitivity and are resistant to obesity elicited by high-fat diet or aging. Inhibition of IP6K1 may afford a therapeutic approach to obesity and diabetes.

Hormonal and Metabolic Effects of Olanzapine and Clozapine Related to Body Weight in Rodents

Objective: To characterize a model of atypical antipsychotic drug‐induced obesity and evaluate its mechanism.

Repeated sucrose access influences dopamine D2 receptor density in the striatum

A decrease in D2 dopamine receptor subtype (D2R) binding in the striatum has been reported in obese individuals and drug addicts. We examined D2R density in the striatum of food-restricted rats that had contingent access to food with different incentive values. Results showed that animals receiving limited access to 0.3u2009M sucrose paired 2u2009h with a chow meal for 7 days had a significantly lower D2R binding in nucleus accumbens shell and dorsolateral striatum compared with animals that had limited access to chow. There was no differential binding, however, in the accumbens core in any of the groups. These findings indicate that feeding conditions and sucrose intake influence D2R density specifically in subregions of the striatum.

Dopamine and binge eating behaviors

Central dopaminergic mechanisms are involved in the motivational aspects of eating and food choices. This review focuses on human and animal data investigating the importance of dopamine on binge eating behaviors. Early work examining dopamine metabolites in the cerebrospinal fluid and plasma of bulimic individuals suggested decreased dopamine turnover during the active phase of the illness. While neuroimaging studies of dopamine mechanisms in bulimia nervosa (BN) and binge eating disorder (BED) are limited, genetic studies in humans have implicated an increased frequency of dopamine transporter and associated D2 receptor polymorphisms with binge pathology. Recent studies in rodent models of dietary-induced binge eating (DIBE) have investigated plausible dopamine mechanisms involved in sustaining binge eating behaviors. In DIBE models, highly palatable foods (fats, sugars and their combination), as well as restricted access conditions appear to promote ingestive responses and result in sustained dopamine stimulation within the nucleus accumbens. Taken together with studies on the comorbidity of illicit drug use and eating disorders, the data reviewed here support a role for dopamine in perpetuating the compulsive feeding patterns of BN and BED. As such, we propose that sustained stimulation of the dopamine systems by bingeing promoted by preexisting conditions (e.g., genetic traits, dietary restraint, stress, etc.) results in progressive impairments of dopamine signaling. To disrupt this vicious cycle, novel research-based treatment options aiming at the neural substrates of compulsive eating patterns are necessary.

Alterations in blood glucose levels under hyperinsulinemia affect accumbens dopamine

Dopaminergic systems have been implicated in diabetes and obesity. Notwithstanding, the most basic relationship between dopamine and plasma insulin as well as glucose levels yet remains unknown. The present experiments were designed to investigate the effects of acute hyperinsulinemia on basal dopamine levels in the nucleus accumbens of the rat under chloral hydrate anesthesia using acute microdialysis in combination with the hyperinsulinemic-glycemic clamping procedure. In Experiment 1, each rat was infused with one of the three concentrations of insulin (2.4, 4.8, or 9.6 mU/kg per min) while plasma glucose levels were maintained at euglycemia (approximately 5.5 mmol/L). Dopamine, dihydroxyphenylacetic acid and homovanillic acid were not significantly different from baseline during either the clamp or post-clamp periods for all insulin concentrations. In Experiment 2, rats were infused with the highest concentration of insulin (9.6 mU/kg per min) and plasma glucose levels were maintained at either hypoglycemia (approximately 3 mmol/L) or hyperglycemia (approximately 14 mmol/L). Dopamine was elevated at 100 min (+113% above basal levels) and 120 min (+117%) in the hypoglycemic condition and at 120 min (+121%) in the hyperglycemic condition. In the hyperglycemic post-clamp period, homovanillic acid was decreased below basal levels (approximately -32%). These results together suggest that short-term blood glucose deviations coupled with acute hyperinsulinemia affect the mesoaccumbens dopamine system.

Acute methylphenidate treatments reduce sucrose intake in restricted-fed bingeing rats

Recent evidence suggests that methylphenidate HCl may be effective at limiting the frequency and the amount of binge eating. The present study investigated if daily treatments with methylphenidate reduced the bingeing-like behavior observed in restricted-fed adult male rats. Three groups (n = 6) received peripheral injections of methylphenidate in doses of 1.5 or 0.75 mg/kg/day, or saline, 3 days prior and 7 days during a previously characterized intermittent feeding regimen that results in a gradual increase of sucrose and food intake. The higher, but not the lower, dose of methylphenidate reduced sucrose intake to an asymptotic level starting after 3 days of the feeding protocol and concurrently led to an increase in the intake of chow. The high dose methylphenidate group also had two-fold lower plasma insulin levels compared with the saline-treated animals at the time of sacrifice on the last day of the feeding regimen. Further histological assays revealed that the methylphenidate treatments, irrespective of the dose used, resulted in selectively higher dopamine transporter and D2-like receptor labeled bindings in the shell region of the nucleus accumbens. These results suggest that relatively low-dose methylphenidate treatments may be effective for the management of binge eating by reducing the intake of palatable foods and may not interfere with short-term regulation of energy balance. These findings further support the notion that the mesoaccumbens dopamine system plays an important role in restricted access-induced sucrose bingeing in this rat model.

Oral sensory and cephalic hormonal responses to fat and non-fat liquids in bulimia nervosa.

Sensory evaluation of food involves endogenous opioid mechanisms. Bulimics typically limit their food choices to low-fat safe foods and intermittently lose control and binge on high-fat risk foods. The aim of this study was to determine whether the oral sensory effects of a fat versus a non-fat milk product (i.e., traditional versus non-fat half-and-half) resulted in different subjective and hormonal responses in bulimic women (n=10) compared with healthy women (n=11). Naltrexone (50mg PO) or placebo was administered 1h before, and blood sampling began 30 min prior to and 29 min after, a 3 min portion controlled modified sham-feeding trial. Following an overnight fast, three morning trials (fat, naltrexone; fat, placebo; and non-fat, placebo) were administered in a random double-blind fashion separated by at least 3 days. Overall, there were no differences between Fat and Non-Fat trials. Hunger ratings (p<0.001) and pancreatic polypeptide levels (p<0.05) were higher for bulimics at baseline. Bulimics also had overall higher ratings for nausea (p<0.05), fatty taste (p<0.01), and fear of swallowing (p<0.005). Bulimics had approximately 40% higher total ghrelin levels at all time points (p<0.001). Hormones and glucose levels were not altered by the modified sham-feeding paradigm. Naltrexone, however, resulted in an overall increase in blood glucose and decrease in ghrelin levels in both groups (p<0.05, for both). These data suggest that bulimic women have different orosensory responses that are not influenced by opioid receptor antagonism, evident in hormonal responses, or dependent on the fat content of a similarly textured liquid.