Leptin signaling in adipose tissue: role in lipid accumulation and weight gain

Rationale: The link between obesity, hyperleptinemia, and development of cardiovascular disease is not completely understood. Increases in leptin have been shown to impair leptin signaling via caveolin-1-dependent mechanisms. However, the role of hyperleptinemia versus impaired leptin signaling in adipose tissue is not known. Objective: To determine the presence and significance of leptin-dependent increases in adipose tissue caveolin-1 expression in humans. Methods and Results: We designed a longitudinal study to investigate the effects of increases in leptin on adipose tissue caveolin-1 expression during weight gain in humans. Ten volunteers underwent 8 weeks of overfeeding, during which they gained an average weight of 4.1±1.4 kg, with leptin increases from 7±3.8 to 12±5.7 ng/mL. Weight gain also resulted in changes in adipose tissue caveolin-1 expression, which correlated with increases in leptin (rho=0.79, P=0.01). In cultured human white preadipocytes, leptin increased caveolin-1 expression, which in turn impaired leptin cellular signaling. Functionally, leptin decreased lipid accumulation in differentiating human white preadipocytes, which was prevented by caveolin-1 overexpression. Further, leptin decreased perilipin and fatty acid synthase expression, which play an important role in lipid storage and biogenesis. Conclusions: In healthy humans, increases in leptin, as seen with modest weight gain, may increase caveolin-1 expression in adipose tissue. Increased caveolin-1 expression in turn impairs leptin signaling and attenuates leptin-dependent lowering of intracellular lipid accumulation. Our study suggests a leptin-dependent feedback mechanism that may be essential to facilitate adipocyte lipid storage during weight gain.     

Nuclear inositol 1,4,5-trisphosphate is a necessary and conserved signal for the induction of both pathological and physiological cardiomyocyte hypertrophy

It is well established that inositol 1,4,5-trisphosphate (IP3) dependent Ca(2+) signaling plays a crucial role in cardiomyocyte hypertrophy. However, it is not yet known whether nuclear IP3 represents a Ca(2+) mobilizing pathway involved in this process. The goal of the current work was to investigate the specific role of nuclear IP3 in cardiomyocyte hypertrophic response. In this work, we used an adenovirus construct that selectively buffers IP3 in the nuclear region of neonatal cardiomyocytes. We showed for the first time that nuclear IP3 mediates endothelin-1 (ET-1) induced hypertrophy. We also found that both calcineurin (Cn)/nuclear factor of activated T Cells (NFAT) and histone deacetylase-5 (HDAC5) pathways require nuclear IP3 to mediate pathological cardiomyocyte growth. Additionally, we found that nuclear IP3 buffering inhibited insulin-like growth factor-1 (IGF-1) induced hypertrophy and prevented reexpression of fetal gene program. Together, these results demonstrated that nuclear IP3 is an essential and a conserved signal for both pathological and physiological forms of cardiomyocyte hypertrophy.     

Muscle endothelial-dependent microvascular dysfunction in adulthood due to early postnatal overnutrition

The aims of our study were to investigate effects of postnatal overnutrition, obtained by restricting the number of pups per litter, on microcirculatory reactivity, fat depots, its total percentage and lipid profile. Microvascular reactivity was evaluated in the cremaster muscle of 24 hamsters divided into four groups, with 6 animals in each one: normal (NL) and restricted (RL) litter groups, both at 6th and 21st weeks of age. The NL group had 8-9 pups and the RL 3 pups per litter and to avoid the litter effect, only one animal was used per litter. The results have shown that the RL group had higher velocity of weight, body mass and fat gain compared to the NL one at weeks 6 and 21. Significant differences were also observed on urogenital fat depot, total cholesterol and low density lipoprotein between groups. At the lowest concentration of Ach, the RL group showed smaller arteriolar dilatation at the 21st than at the 6th week [5(3-13) vs 19(8-40)%, p<0.01] while the NL one did not show any difference within the group. The highest concentration of Ach at the 21th week pointed to endothelial-dependent microvascular dysfunction in RL compared to NL [3(8-26) vs. 13(8-26)%, p<0.05]. Endothelial-independent microvascular reactivity was similar between groups. Our data suggest that postnatal overnutrition is associated to muscle endothelial-dependent microvascular dysfunction, greater body mass and total percentage of fat and impaired the lipid profile. In conclusion, the imprinting promoted by this experimental model of obesity was able to influence microvascular reactivity later in life.     

Tongue retraining and occlusal stability in a young adult. Case report

The clinical observation describes the case of a 20-year-old woman who has consulted for aesthetic and functional reasons. She presents a skeletal class III normodivergent, an occlusal class III with a lower proalveoli quite marked. In addition, a lingual dysfunction which manifests itself by important anterior diastema and dento-dental disharmony at the upper jaw complicates the case. The undertaken therapeutic project starts with a first step of a lingual praxis rehabilitation, followed by an orthodontic step and upper lateral incisors-plasty. The purpose of those results is the evaluation of the stability two years later, which was reported positive.     

The interference of the cleaning procedure of root walls with two different solvents on the adhesion of fiberglass intraradicular posts

Aim: This study was undertaken to examine the effect of root canal (RT) sealers content and the cleaning procedure of RT walls on bond strength (BS) of a fiber reinforced composite (FRC) post cemented with resin-based or zinc phosphate cement. Materials and methods: Forty bovine roots were divided into 2 groups (n = 20) and obturated with gutta-percha points plus Sealer 26 sealer or gutta-percha points plus N-Rickert sealer. In each group, half (n = 10) of intracanal walls was cleaned with ethanol and the other half with sulfuric ether. In each of these subgroups, half of intracanal posts (n = 5) were cemented with Bistite resin-based cement and half with zinc phosphate cement. Specimens were submitted to pull-out test and tensile force until post dislodgement. The maximum forces required for post removal was expressed in MPa, means were submitted to statistical analysis (Analysis of Variance Test, a = 0.05). Results: Fiber reinforced composite cemented with zinc phosphate were significantly more retentive than those cemented with Bistite (p < 0.05). Regarding the influence of eugenol-based sealer on post retention, there was a statistically significant difference (p < 0.05) only between groups cemented with Bistite, in which canals filled with N-Rickert + gutta-percha showed lower BS than canals filled with Sealer 26 + gutta-percha. Conclusion: Despite endodontic cement used, higher pull-out bond strength were obtained when posts were cemented with zinc phosphate. Clinical significance: The importance of ethanol or sulphuric ether application to properly replace water from intraradicular dentine still requires further investigations, especially to clarify if this technique may reduce the effect of aging and improve the stability of the bond, when used to cement fiber posts into the root canal. Keywords: Laboratory research, Dentin, Eugenol, Resin cements, Root canal filling material, Pull-out test, Cleaning procedure. How to cite this article: Gomes MF, Botta SB, Matos AB, Garone- Netto N. The Interference of the Cleaning Procedure of Root Walls with Two Different Solvents on the Adhesion of Fiberglass Intraradicular Posts. J Contemp Dent Pract 2012;13(3):275-279. Source of support: Nil Conflict of interest: None declared.     

Distinct roles for long-term hematopoietic stem cells and erythroid precursor cells in a murine model of Jak2V617F-mediated polycythemia vera

In the current model of the pathogenesis of polycythemia vera (PV), the JAK2V617F mutation arises in hematopoietic stem cells (HSCs) that maintain the disease, while erythroid precursor populations expand, resulting in excessive red blood cell production. We examined the role of these specific cell populations using a conditional Jak2V617F knockin murine model. We demonstrate that the most immature long-term (LT) HSCs are solely responsible for initiating and maintaining the disease in vivo and that Jak2V617F mutant LT-HSCs dominate hematopoiesis over time. When we induced Jak2V617F expression in erythropoietin receptor expressing precursor cells, the mice developed elevated hematocrit, expanded erythroid precursors, and suppressed erythropoietin levels. However, the disease phenotype was significantly attenuated compared with mice expressing Jak2V617F in LT-HSCs. In addition to developing a PV phenotype, all mice transplanted with Jak2V617F LT-HSCs underwent myelofibrotic transformation over time. These findings recapitulate the development of post-PV myelofibrosis in human myeloproliferative neoplasms. In aggregate, these results demonstrate the distinct roles of LT-HSCs and erythroid precursors in the pathogenesis of PV.