Summary 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 which regulates glucose homeostasis and protein translation respectively via the GSK3β and mTOR pathways. Thus Akt, mTOR and GSK3β signaling are dramatically augmented in skeletal muscle, white adipose tissue, and liver of mice with targeted deletion of IP6K1. IP7 impacts this pathway by potently inhibiting the PDK1 phosphorylation of Akt, preventing its activation and thereby impacting 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.

ALBAUGH, VANCE L., CATHY R. HENRY, NICHOLAS T. BELLO, ANDRAS HAJNAL, SUSAN L. LYNCH, BETH HALLE, AND CHRISTOPHER J. LYNCH. Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity. 2006; 14:36 -51. Objective: To characterize a model of atypical antipsychotic drug-induced obesity and evaluate its mechanism. Research Methods and Procedures: Chronically, olanzapine or clozapine was self-administered via cookie dough to rodents (Sprague-Dawley or Wistar rats; C57Bl/6J or A/J mice). Chronic studies measured food intake, body weight, adiponectin, active ghrelin, leptin, insulin, tissue wet weights, glucose, clinical chemistry endpoints, and brain dopaminergic D2 receptor density. Acute studies examined food intake, ghrelin, leptin, and glucose tolerance. Results: Olanzapine (1 to 8 mg/kg), but not clozapine, increased body weight in female rats only. Weight changes were detectable within 2 to 3 days and were associated with hyperphagia starting ϳ24 hours after the first dose. Chronic administration (12 to 29 days) led to adiposity, hyperleptinemia, and mild insulin resistance; no lipid abnormalities or changes in D2 receptor density were observed. Topiramate, which has reversed weight gain from atypical antipsychotics in humans, attenuated weight gain in rats. Acutely, olanzapine, but not clozapine, lowered plasma glucose and leptin. Increases in glucose, insulin, and leptin following a glucose challenge were also blunted. Discussion: A model of olanzapine-induced obesity was characterized which shares characteristics of patients with atypical antipsychotic drug-induced obesity; these characteristics include hyperphagia, hyperleptinemia, insulin resistance, and weight gain attenuation by topiramate. This model may be a useful and inexpensive model of uncomplicated obesity amenable to rapid screening of weight loss drugs. Olanzapine-induced weight gain may be secondary to hyperphagia associated with acute lowering of plasma glucose and leptin, as well as the inability to increase plasma glucose and leptin following a glucose challenge.

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 0.3 M sucrose paired 2 h 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.