Adipocyte PU.1 knockout promotes insulin sensitivity in HFD-fed obese mice.

Insulin resistance is a key feature of obesity and type 2 diabetes. PU.1 is a master transcription factor predominantly expressed in macrophages but after HFD feeding PU.1 expression is also significantly increased in adipocytes. We generated adipocyte specific PU.1 knockout mice using adiponectin cre to investigate the role of PU.1 in adipocyte biology, insulin and glucose homeostasis. In HFD-fed obese mice systemic glucose tolerance and insulin sensitivity were improved in PU.1 AKO mice and clamp studies indicated improvements in both adipose and liver insulin sensitivity. At the level of adipose tissue, macrophage infiltration and inflammation was decreased and glucose uptake was increased in PU.1 AKO mice compared with controls. While PU.1 deletion in adipocytes did not affect the gene expression of PPARg itself, we observed increased expression of PPARg target genes in eWAT from HFD fed PU.1 AKO mice compared with controls. Furthermore, we observed decreased phosphorylation at serine 273 in PU.1 AKO mice compared with fl/fl controls, indicating that PPARg is more active when PU.1 expression is reduced in adipocytes. Therefore, in obesity the increased expression of PU.1 in adipocytes modifies the adipocyte PPARg cistrome resulting in impaired glucose tolerance and insulin sensitivity

PROYEK PEMBANGUNAN RUMAH SUSUN SEDERHANA SEWA DI YOGYAKARTA

Rumah susun sederhana sewa adalah bangunan gedung bertingkat yang ditujuan sebagai alternatif pemenuhan kebutuhan rumah yang layak huni untuk masyarakat golongan kelas menengah ke bawah. Ada tiga aspek yang akan dibahas dalam perencanaan proyek pembangunan rumah susun sederhana sewa DI Yogyakarta yang berjumlah 5 lantai ini yaitu, perencanaa drainase dan pemipaan air bersih analisis dampak lalu lintas, serta perkiraan biaya dan waktu konstruksi. Perencanaan drainase dan pemipaan mencakup perhitungan kebutuhan air bersih, dimensi pipa, dimensi tangki, kebutuhan pompa, pembuatan jalur isometri dan perencanaan drainase serta pengaliran air hujan dalam kawasan gedung. Untuk analisis dampak lalu lintas mencakup kondisi lalu lintas sebelum dan sesudah pembangunan serta perencanaan ruang parkir dan area pejalan kaki. Sedangkan untuk perencanaan manajemen biaya dan waktu, yaitu mulai dari menghitung volume setiap pekerjaan, menentukan harga satuan pekerjaan, rencana anggaran biaya, menentukan durasi pekerjaan, menentukan jumlah pekerja, jumlah material, ketergantungan proyek, kurva s dan menganalisa Critical Path Method. Data yang digunakan dalam perencanaan ini diperoleh dari dosen pengajar berupa data sekunder yang meliputi denah eksisting, denah perencanaan (site plan), data curah hujan dan beberapa data lainnya. Dalam perhitungan kebutuhan air bersih diperoleh Qd = 142560 lt/hari, Qh = 17820 lt/jam, Qh-maks = 35640 lt/jam dan Qm-max = 1188 lt/menit. Diameter pipa yang digunakan yaitu 0,75 inch, 1 inch, 1,25 inch, 1,5 inc dan 2 inch. Kapasitas total ground water tank dengan rata-rata jangka waktu pemakaian 8 jam didapatkan 77 m3 dan untuk rooftank 12 m3. Besarnya daya pompa untuk bangunan rumah susun yang didapatkan ialah 792,996 watt dan untuk daya pompa pada bangunan food court sebesar 731,44 watt. Bak penampungan air hujan yang digunakan berjumlah 17 buah dengan bentuk tabung dengan diameter 1 meter serta tinggi 4 meter. Jam puncak lalu lintas pada ruas jalan yang ditinjau adalah 16.00-17.00. Rencana parkir dan yang telah direncanakan memiliki selisih sebesar 94 unit sepeda motor dan 37 unit mobil. Maka perlu penambahan Kawasan untuk area parkir. Dari hasil analisis, tingkat pelayanan pada ruas Jalan Ki Ageng Pemanahan masih berada pada kinerja jalan yang baik (ITP B). Rencana anggaran biaya (RAB ), untuk menyelesaikan proyek pembangunan Rumah Susun Sederhana Sewa hingga tahap akhir membutuhkan biaya Rp 44.002.186.000 ( Empat Puluh Empat Miliar Dua Juta Seratus Delapan Puluh Enam Ribu Rupiah). Diestimasikan penyelesaian pembangunan Rumah Susun Sederhana Sewa membutuhkan waktu 490 har

Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of atherogenic lipoproteins

Loss-of-function mutations in hepatocyte nuclear factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare, protein-coding HNF1A variant, most of unknown functional consequence. To characterize the full allelic series, we performed deep mutational scanning of 11,970 protein-coding HNF1A variants in human hepatocytes and clinical correlation with 553,246 exome-sequenced individuals. Surprisingly, we found that ∼1:5 rare protein-coding HNF1A variants in the general population cause molecular gain of function (GOF), increasing the transcriptional activity of HNF1A by up to 50% and conferring protection from type 2 diabetes (odds ratio [OR] = 0.77, p = 0.007). Increased hepatic expression of HNF1A promoted a pro-atherogenic serum profile mediated in part by enhanced transcription of risk genes including ANGPTL3 and PCSK9. In summary, ∼1:300 individuals carry a GOF variant in HNF1A that protects carriers from diabetes but enhances hepatic secretion of atherogenic lipoproteins.publishedVersio

Exosomes as mediators of intercellular crosstalk in metabolism.

Exosomes are nanoparticles secreted by all cell types and are a large component of the broader class of nanoparticles termed extracellular vesicles (EVs). Once secreted, exosomes gain access to the interstitial space and ultimately the circulation, where they exert local paracrine or distal systemic effects. Because of this, exosomes are important components of an intercellular and intraorgan communication system capable of carrying biologic signals from one cell type or tissue to another. The exosomal cargo consists of proteins, lipids, miRNAs, and other RNA species, and many of the biologic effects of exosomes have been attributed to miRNAs. Exosomal miRNAs have also been used as disease biomarkers. The field of exosome biology and metabolism is rapidly expanding, with new discoveries and reports appearing on a regular basis, and it is possible that potential therapeutic approaches for the use of exosomes or miRNAs in metabolic diseases will be initiated in the near future

HIF-2α Preserves Mitochondrial Activity and Glucose Sensing in Compensating β-Cells in Obesity.

In obesity, increased mitochondrial metabolism with the accumulation of oxidative stress leads to mitochondrial damage and β-cell dysfunction. In particular, β-cells express antioxidant enzymes at relatively low levels and are highly vulnerable to oxidative stress. Early in the development of obesity, β-cells exhibit increased glucose-stimulated insulin secretion in order to compensate for insulin resistance. This increase in β-cell function under the condition of enhanced metabolic stress suggests that β-cells possess a defense mechanism against increased oxidative damage, which may become insufficient or decline at the onset of type 2 diabetes. Here, we show that metabolic stress induces β-cell hypoxia inducible factor 2α (HIF-2α), which stimulates antioxidant gene expression (e.g., Sod2 and Cat) and protects against mitochondrial reactive oxygen species (ROS) and subsequent mitochondrial damage. Knockdown of HIF-2α in Min6 cells exaggerated chronic high glucose-induced mitochondrial damage and β-cell dysfunction by increasing mitochondrial ROS levels. Moreover, inducible β-cell HIF-2α knockout mice developed more severe β-cell dysfunction and glucose intolerance on a high-fat diet, along with increased ROS levels and decreased islet mitochondrial mass. Our results provide a previously unknown mechanism through which β-cells defend against increased metabolic stress to promote β-cell compensation in obesity