Inhibition of mouse brown adipocyte differentiation by second-generation antipsychotics

Brown adipose tissue is specialized to burn lipids for thermogenesis and energy expenditure. Second-generation antipsychotics (SGA) are the most commonly used drugs for schizophrenia with several advantages over first-line drugs, however, it can cause clinically-significant weight gain. To reveal the involvement of brown adipocytes in SGA-induced weight gain, we compared the effect of clozapine, quetiapine, and ziprasidone, SGA with different propensities to induce weight gain, on the differentiation and the expression of brown fat-specific markers, lipogenic genes and adipokines in a mouse brown preadipocyte cell line. On Oil Red-O staining, the differentiation was inhibited almost completely by clozapine (40 microM) and partially by quetiapine (30 microM). Clozapine significantly down-regulated the brown adipogenesis markers PRDM16, C/EBPbeta, PPARgamma2, UCP-1, PGC-1alpha, and Cidea in dose- and time-dependent manners, whereas quetiapine suppressed PRDM16, PPARgamma2, and UCP-1 much weakly than clozapine. Clozapine also significantly inhibited the mRNA expressions of lipogenic genes ACC, SCD1, GLUT4, aP2, and CD36 as well as adipokines such as resistin, leptin, and adiponectin. In contrast, quetiapine suppressed only resistin and leptin but not those of lipogenic genes and adiponectin. Ziprasidone (10 microM) did not alter the differentiation as well as the gene expression patterns. Our results suggest for the first time that the inhibition of brown adipogenesis may be a possible mechanism to explain weight gain induced by clozapine and quetiapine.

Defect of Acid-base Transporters in Distal Renal Tubular Acidosis / 대한신장학회잡지

The purpose of this study was to elucidate whether the molecular defect of acid-base transporters in renal tubules is related to the functional defect of urinary acidification in distal renal tubular acidosis(RTA). We performed NH4Cl, furosemide, or bicarbonate loading test to evaluate renal acidification function, and immunohistochemistry using antibodies to H+- ATPase, Cl-/HCO3- exchanger(band-3 protein), and Na+/K+-ATPase in kidney tissue in 6 patients with RTA and renal cell carcinoma patients as normal controls. Kidney tissue was obtained either by percutaneous needle biopsy(RTA) or nephrectomy(NC). The results were as follows; 1) In all six RTA patients, proton secretory defect of distal acidification was shown by a failure to lower the urine pH after NH4Cl loading or furosemide test or abnormally low urine-blood pCO2 difference during bicarbonate loading. In two patients with RTA, proximal acidification defect was combined, which was demonstrated by increased fractional excretion of bicarbonate. 2) In normal control, intense H+-ATPase and band-3 protein staining was observed in collecting ducts. 3) In distal RTA patients, H+-ATPase and band- 3 protein staining was not demonstrable or markedly decreased in the intercalated cells of distal nephron. 4) In two patients who had both proximal and distal RTA, H+-ATPase staining was markedly decreased in the brush border of proximal tubules as well as the distal nephron. In conclusion, the defect of acid-base transporters in renal tubule was related with the functional defect of urinary acidification in distal RTA.

Lymphocyte Subsets in Patients with Hepatitis B Virus Associated Glomerulonephritis / 대한신장학회잡지

Immune complex formation has been recently emphasized as an important pathogenetic mechanism of hepatitis B virus associated glomerulonephritis (HBGN), but little are known on the role of cell- mediated immunity in that disease. In this study, we measured lymphocyte subsets of the blood samples from three groups(HBGN group, healthy control group, hepatitis B group without renal disease) by flow cytometry in order to clarify abnormalities in immune regulatory system of HBGN. The results were as follows: 1) To compare between HBGN and healthy control group, the proportion of CD4+ cells were higher for HBGN than for healthy control but that of B lymphocytes were lower for HBGN than for healthy control. Between HBGN and hepatitis B group without renal disease, the proportion of B lymphocytes were higher for HBGN but that of NK cells were lower for HBGN(P<0.05). 2) To compare the male data of the three groups, the percentage of CD4+ cells in HBGN group were higher and the percentage of B lymphocytes were lower than healthy control. Between HBGN group and hepatitis B group without renal disease, no significant difference were noted in CD4+ cells, CD8+ cells, B lymphocytes, NK cells and CD4/CD8 ratio (P<0.05). 3) HBGN patients with membraneous nephropathy (MN) showed higher proportion of CD4+ cells than those with membranoproliferative glomerulonephritis (MPGN)(P<0.05). But, no difference was observed between HBGN patients with and without nephrotic syndrome. Nor between HBGN patients with and without HBe antigenemia. In conclusion, above result implies the pathogenetic role of cell-mediated immunity in HBGN. Analysis of lymphocyte subsets for each stage of HBGN, together with the assay of lymphocyte activation markers is required in the future.