lem. There are about one billion adults that are overweight with a body mass index (BMI) over 25, and 300 million are obese with a BMI over 30 (http://www.who.int). Today there are more people overweight than underweight. It causes costly health problems, reduces life expectancy, and is associated with stigma and discrimination, which has a major effect on the quality of life. Obesity and overweight substantially increase the risk of morbidity from hypertension, dyslipidemia, type 2 diabetes, and coronary heart disease. Obesity is also important for the development of obstructive sleep apnea and respiratory problems, gallbladder disease, osteoarthritis, and nonalcoholic fatty liver disease as well as endometrial, breast, prostate, and colon cancers.There are several genes associated with obesity on the human obesity map (1) such as the melanocortin 4 receptor (MC4R), leptin and the leptin receptor. However, the contribution of each specific gene to obesity is low, being highest for the MC4R gene ranging from 1-6% (2). The overall inheritability of BMI is estimated to be about 50 -60%. Recently, three reports have shown a strong association of a singlenucleotide polymorphism (SNP) in a gene called FTO with both childhood and adult obesity. Frayling and colleagues (3) performed a genome-wide association study for about 490,000 autosomal SNPs in a type 2 diabetes population in the United Kingdom. They found that SNP rs9939609 in the FTO gene was strongly associated with type 2 diabetes, but this allele was also strongly associated with an increased BMI. The association between this FTO SNP and type 2 diabetes was abolished by adjustment for the BMI, suggesting that it was due to the increased BMI. The association of this variant with the BMI was replicated in 13 cohorts with over 38,000 individuals. Interestingly, 16% of the adults who were homozygous for this SNP weighed about 3 kg more and had 1.67-fold increased odds of obesity. This association was observed from age 7 yr upward, and it reflects a specific increase in fat mass (3). Independently, Dina et al. (4) found another SNP, rs1121980, in the first intron of the FTO gene, that was strongly associated with severe (BMI Ͼ 40) adult obesity with odds ratio of 1.55 in a population of French individuals of European ancestry). Further genotyping showed a similarly strong association of several SNPs in a cohort of about 900 severely obese adults and 2700 nonobese French controls. Three of the four most significantly associated SNPs (rs17817449, rs3751812, and rs1421085) are puta-
Background: Polymorphism in the FTO gene is strongly associated with obesity, but little is known about the molecular bases of this relationship. We investigated whether hypothalamic FTO is involved in energy-dependent overconsumption of food. We determined FTO mRNA levels in rodent models of short-and long-term intake of palatable fat or sugar, deprivation, diet-induced increase in body weight, baseline preference for fat versus sugar as well as in same-weight animals differing in the inherent propensity to eat calories especially upon availability of diverse diets, using quantitative PCR. FTO gene expression was also studied in organotypic hypothalamic cultures treated with anorexigenic amino acid, leucine. In situ hybridization (ISH) was utilized to study FTO signal in reward-and hunger-related sites, colocalization with anorexigenic oxytocin, and c-Fos immunoreactivity in FTO cells at initiation and termination of a meal.
Oxytocin (OT) facilitates feeding termination stemming from high osmolality, stomach distention, and malaise. Recent knockout (KO) studies suggested a crucial function for OT in carbohydrate intake: OT-/- mice had increased preference for carbohydrates, including sucrose, but not fat (Intralipid). In striking contrast, sugar appetite was unaffected in the OT receptor KO mouse; data from wild-type animals have been insufficient. Therefore, we examined the involvement of OT in the regulation of sucrose vs. fat intake in C57BL/6 mice that served as a background KO strain. We exposed mice to a meal of sucrose or Intralipid and determined that the percentage of c-Fos-immunoreactive paraventricular hypothalamic OT neurons was elevated at termination of intake of either of the tastants, but this increase was 2-fold higher in sucrose-fed mice. A 48-h exposure to sucrose compared with Intralipid caused up-regulation of OT mRNA, whereas inherent individual preferences for sucrose vs. fat were not associated with differences in baseline OT expression as established with quantitative PCR. We found that L-368,899, an OT receptor antagonist, increased sugar intake when sucrose was presented alone or concurrently with Intralipid; it had no effect on Intralipid or total calorie consumption. L-368,899 affected Fos immunoreactivity in the paraventricular hypothalamus, arcuate nucleus, amygdala, and nucleus of the solitary tract, areas involved in aversion, satiety, and reward. This pattern serves as neuroanatomical basis of OT's complex role in food intake, including sucrose intake. The current findings expand our knowledge on OT and suggest that it acts as a carbohydrate-specific inhibitor of feeding.
The presence of a well-developed contractile apparatus is the feature determining major roles of podocytes in the renal glomeruli. Receptors for a variety of vasoactive hormones are expressed in these cells; however, most of the signaling pathways are still unknown and remain to be elucidated. Angiotensin II (Ang II) and atrial natriuretic peptide (ANP), due to their opposite action, are the major modulators of glomerular filtration. In podocytes, Ang II induces rise in intracellular calcium concentration, whereas ANP stimulates generation of cGMP. The present study was designed to check whether ANP-stimulated cGMP synthesis in podocytes might be affected by Ang II. Cultured rat (RP) and mouse (MP) podocytes were stimulated with ANP, in the absence or presence of Ang II and cyclic GMP was determined by RIA method. Co-incubation of podocytes with ANP and Ang II caused significant (p < 0.01) suppression of ANP-dependent cGMP generation. The effect was prevented by saralasin, an inhibitor of angiotensin receptors. Phorbol-12-myristate-13-acetate (PMA) mimicked, whereas chelerythrine reversed inhibitory effect of Ang II. In conclusion, angiotensin II counteracts ANP-stimulated cGMP synthesis in cultured podocytes. It seems likely that the protein kinase C pathway is involved in this effect.
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