Nucleus Accumbens D1 Receptor-Expressing Spiny Projection Neurons Control Food Motivation and Obesity.

BACKGROUND: Obesity is a chronic relapsing disorder that is caused by an excess of caloric intake relative to energy expenditure. There is growing recognition that food motivation is altered in people with obesity. However, it remains unclear how brain circuits that control food motivation are altered in obese animals. METHODS: Using a novel behavioral assay that quantifies work during food seeking, in vivo and ex vivo cell-specific recordings, and a synaptic blocking technique, we tested the hypothesis that activity of circuits promoting appetitive behavior in the core of the nucleus accumbens (NAc) is enhanced in the obese state, particularly during food seeking. RESULTS: We first confirmed that mice made obese with ad libitum exposure to a high fat diet work harder than lean mice to obtain food, consistent with an increase in food motivation in obese mice. We observed greater activation of D1 receptor-expressing NAc spiny projection neurons (NAc D1SPNs) during food seeking in obese mice relative to lean mice. This enhanced activity was not observed in D2 receptor-expressing neurons (D2SPNs). Consistent with these in vivo findings, both intrinsic excitability and excitatory drive onto D1SPNs were enhanced in obese mice relative to lean mice, and these measures were selective for D1SPNs. Finally, blocking synaptic transmission from D1SPNs, but not D2SPNs, in the NAc core decreased physical work during food seeking and, critically, attenuated high fat diet-induced weight gain. CONCLUSIONS: These experiments demonstrate the necessity of NAc core D1SPNs in food motivation and the development of diet-induced obesity, establishing these neurons as a potential therapeutic target for preventing obesity.

Effect of glutamine on the initiation and promotion phases of DMBA-induced mammary tumor development.

BACKGROUND: Oral glutamine (GLN) has been shown to up-regulate tissue glutathione (GSH), augment natural killer (NK) cell activity, and prevent tumor growth in an implantable breast cancer model (MTF-7). We hypothesized that dietary GLN would likewise antagonize the induction or promotion of tumor formation by 7,12-dimethylbenz[a]anthracene (DMBA) via up-regulation of GSH or augmentation of NK activity. METHODS: At age 55 days, 81 Sprague-Dawley rats were gavaged with a one-time dose of 80 mg/kg DMBA, time 0. Rats were randomized into 3 groups (GLN+DMBA, Freamine [FA]+DMBA, water (H2O)+DMBA), pair-fed chow, and gavaged with 1.0 g/kg/day GLN or isonitrogenous amount of FA or H2O for the indicated times: PreFed (-1 to + 16 weeks), Short-Fed (-1 to + 1 weeks) and PostFed (+ 1 to +16 weeks). After 16 weeks, rats were killed and examined for mammary tumors, blood was assayed for GLN and GSH content, and spleens were assayed for NK cytotoxicity. RESULTS: Over the 4-month study period, there was no significant difference in tumorigenesis between FA and H2O groups, regardless of timing of feeding and amino acid diet, except GLN. In Pre- and PostFed GLN groups, there was no significant difference between groups, but there were significant decreases in tumorigenesis in GLN groups compared with either FA or H2O groups. However, in the Short-Fed group, there was no significant difference in tumorigenesis from the GLN, FA, or H2O groups. CONCLUSIONS: Continuously supplemented GLN significantly reduced DMBA-induced breast cancer growth when compared with the non-GLN-supplemented and Short-Fed supplemental GLN groups. Furthermore, GLN appears to have its primary effect on promotion and not initiation of tumor formation. This decreased tumor formation was associated with significantly higher arterial GLN and GSH levels and NK activity at killing in the GLN+DMBA group. Protein in the presentation of FA did not promote or prevent tumor growth. These data indicate that GLN may be useful in the chemoprevention of breast cancer.

Diffuse giant inflammatory polyposis: a challenging clinicopathologic diagnosis.

Giant inflammatory polyposis of the colon is an uncommon manifestation of inflammatory bowel disease. We report a unique case of localized diffuse giant inflammatory polyposis in a 58-year-old white man, which was characterized by recurrence following initial surgical resection. The patient presented with symptoms of abdominal pain and passing blood per rectum. Colonoscopic examination revealed a near-obstructing, "fungating" mass in the sigmoid colon, which clinically was thought to represent colon carcinoma. Histology of several colon biopsies revealed marked acute inflammation with microabscess formation of the polyps and the adjacent mucosa. There was no evidence of dysplasia or malignancy. Because malignancy was strongly suspected and to relieve the obstructive symptoms, the patient underwent a segmental colectomy. The histologic features of the resected mass showed giant polyps with acute inflammation diagnostic of giant inflammatory polyposis. Again, there was no evidence of malignancy. Seven months later, following an uneventful initial postoperative recovery, the patient developed a recurrence of the mass with obstructive symptoms and required further surgical resection. The gross and histologic features of the lesion were similar to the previous findings. This case highlights the varied presenting symptoms and deceptive gross colonoscopic and radiologic features of localized diffuse giant inflammatory polyposis. Finally, the presence of inflammation at the resection margins appears to predict recurrence or persistence of the disease.

HIV and plasmablastic lymphoma manifesting in sinus, testicles, and bones: a further expansion of the disease spectrum.

Patients with HIV infection are at increased risk for B-cell neoplasms and plasma cell dyscrasias. Both B cell and plasma cell tumors tend to be intermediate or high grade and are frequently associated with Epstein-Barr virus. Patients with HIV infection are also at higher risk of acquiring plasmablastic lymphoma. Until this time, only sinus, oral gastrointestinal, and lung manifestation have been noted. In this report we describe a 41-year-old male with HIV infection who developed multiple pleomorphic, extramedullary plasmablastic lymphomas associated with Epstein-Barr virus. We review the clinical and immunological features of his malignancy and thereby expand the spectrum of disease to include additional sites (bones, testicles) not previously reported.

Inhibitory effect of candesartan and rosuvastatin on CD40 and MMPs expression in apo-E knockout mice: novel insights into the role of RAS and dyslipidemia in atherogenesis.

BACKGROUND: There is increasing evidence of cross-talk between renin-angiotensin system (RAS) and dyslipidemia in atherogenesis mediated via activation of inflammatory cascade, involving CD40 and matrix metalloproteinases (MMPs). We postulated that inhibition of RAS with candesartan and dyslipidemia with rosuvastatin would have additive inhibitory effect on CD40 and MMPs expression and atherogenesis. METHODS AND RESULTS: Apo-E knockout mice were fed high-cholesterol diet alone, or with candesartan or rosuvastatin or both. C57BL/6J mice on regular mice chow served as control. Twelve weeks later, apo-E knockout mice with high-cholesterol diet had extensive atherosclerosis, whereas C57BL/6J mice had no atherosclerosis. Candesartan and rosuvastatin alone decreased the extent of atherosclerosis. However, the combined feeding of candesartan and rosuvastatin reduced atherosclerosis in an additive fashion. The expression of CD40 and MMPs was found to be up-regulated in apo-E knockout mice. While candesartan and rosuvastatin each had a small inhibitory effect on the expression of CD40 and MMPs, the combination completely blocked the up-regulation of these inflammatory mediators. CONCLUSION: This study, for the first time, demonstrates that the combination of candesartan and rosuvastatin markedly affects the expression of CD40 and MMPs, resulting in a greater anti-atherosclerotic effect.