Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin's glucose-lowering effects.

Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined. We demonstrate that the expression of APLNR (APJ/AGTRL1), the only known receptor for apelin, is predominantly restricted to the endothelial cells (ECs) of multiple adult metabolic organs, including skeletal muscle and adipose tissue. Conditional endothelial-specific deletion of Aplnr (AplnrECKO ) resulted in markedly impaired glucose utilization and abrogation of apelin-induced glucose lowering. Furthermore, we identified inactivation of Forkhead box protein O1 (FOXO1) and inhibition of endothelial expression of fatty acid (FA) binding protein 4 (FABP4) as key downstream signaling targets of apelin/APLNR signaling. Both the Apln-/- and AplnrECKO mice demonstrated increased endothelial FABP4 expression and excess tissue FA accumulation, whereas concurrent endothelial Foxo1 deletion or pharmacologic FABP4 inhibition rescued the excess FA accumulation phenotype of the Apln-/- mice. The impaired glucose utilization in the AplnrECKO mice was associated with excess FA accumulation in the skeletal muscle. Treatment of these mice with an FABP4 inhibitor abrogated these metabolic phenotypes. These findings provide mechanistic insights that could greatly expand the therapeutic repertoire for type 2 diabetes and related metabolic disorders.

In Vivo Changes of Breast Perfusion After Augmentation.

BACKGROUND: Revision surgeries after breast augmentation are associated with an increased risk of complications (eg, nipple areolar complex [NAC]) necrosis. Consequently, maintaining perfusion to the NAC is a critical aspect of secondary breast surgery. OBJECTIVES: The purpose of this study was to examine in vivo changes in perfusion to the NAC after implant breast augmentation using magnetic resonance imaging (MRI) technology. METHODS: High-resolution 3 Tesla MRI images of 10 women (20 breasts) with previous breast augmentation were compared to a control population of 15 women (30 breasts). Perforators from the internal mammary artery and lateral thoracic artery were examined for the diameter of the originating perforator, distance between the nipple and most distally visualized point of the medial and lateral perforator, and dominance pattern between the medial vs lateral perforators. RESULTS: No difference was found in the caliber of the medial vessels in the implant group compared to the control group. In contrast, the caliber of the lateral blood vessels trended towards being 20% larger in diameter in the augmented breasts. The distances between the nipple and the medial and lateral vessels increased. The frequencies in the distribution of dominance were not significantly different between the implant group and the control group. CONCLUSIONS: Overall, medial and lateral blood supply to the NAC are preserved in the augmented patient. Our results suggest a slight delay effect that seems to increase the caliber of the lateral perforators. In addition, the tissue expansion provided by the implants effectively increases the length of both perforators. LEVEL OF EVIDENCE: 3 Therapeutic.

SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation.

White adipose tissue (WAT) is essential for maintaining metabolic function, especially during obesity. The intronic microRNAs miR-33a and miR-33b, located within the genes encoding sterol regulatory element-binding protein 2 (SREBP-2) and SREBP-1, respectively, are transcribed in concert with their host genes and function alongside them to regulate cholesterol, fatty acid, and glucose metabolism. SREBP-1 is highly expressed in mature WAT and plays a critical role in promoting in vitro adipocyte differentiation. It is unknown whether miR-33b is induced during or involved in adipogenesis. This is in part due to loss of miR-33b in rodents, precluding in vivo assessment of the impact of miR-33b using standard mouse models. This work demonstrates that miR-33b is highly induced upon differentiation of human preadipocytes, along with SREBP-1. We further report that miR-33b is an important regulator of adipogenesis, as inhibition of miR-33b enhanced lipid droplet accumulation. Conversely, overexpression of miR-33b impaired preadipocyte proliferation and reduced lipid droplet formation and the induction of peroxisome proliferator-activated receptor γ (PPARγ) target genes during differentiation. These effects may be mediated by targeting of HMGA2, cyclin-dependent kinase 6 (CDK6), and other predicted miR-33b targets. Together, these findings demonstrate a novel role of miR-33b in the regulation of adipocyte differentiation, with important implications for the development of obesity and metabolic disease.

Radiation therapy and expander-implant breast reconstruction: an analysis of timing and comparison of complications.

BACKGROUND: The optimal timing of expander-implant exchange in the setting of postmastectomy radiation therapy (PMRT) remains unclear with prior reports yielding inconsistent and variable results. The purpose of this study was to characterize complications associated with the sequencing of expander-implant breast reconstruction before or after PMRT and to compare the outcomes between early (<4 months) and late (>4 months) expander-implant exchange in the subset of patients who received PMRT before exchange. MATERIALS AND METHODS: The medical records of all patients PMRT in the setting of tissue expander-implant breast reconstruction between June 2004 and June 2011 at our institution were reviewed retrospectively. Patients were first classified as having undergone expander-implant exchange before the initiation of PMRT or after the completion of PMRT. Patients who underwent expander-implant exchange after PMRT were then classified as having undergone exchange early (<4 months after PMRT) or late (>4 months after PMRT). All complications requiring additional surgery or hospitalization were recorded. RESULTS: Fifty-five eligible patients were identified as having undergone 56 two-stage tissue expander-implant breast reconstructions. Twenty-two reconstructions underwent exchange before PMRT and 34 reconstructions underwent exchange after PMRT. There was no significant difference in overall complication rate (54.55% vs 47.06%, P = 0.785) or reconstruction failure rate (13.64% vs 20.59%, P = 0.724) between the 2 cohorts. Twenty reconstructions underwent exchange less than 4 months after PMRT and 14 underwent exchange more than 4 months after PMRT. There was no significant difference in overall complication rate (40% vs 57.14%, P = 0.487) or failure rate (25% vs 14.29%, P = 0.672) between the 2 groups. Trends suggest a higher rate of infection in patients who underwent exchange earlier (30% vs 14.29%, P = 0.422) and a higher rate of capsular contracture in patients who underwent exchange later (5% vs 21.43%, P = 0.283); however, statistical significance was not reached. CONCLUSIONS: Our findings suggest that neither the sequencing nor timing of expander-implant exchange in the setting of PMRT affects overall complication or reconstruction failure rate. However, the timing of exchange may impact the type of complication encountered. Further investigation is necessary to determine an optimal time for expander-implant exchange.