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A fluorinated peptide with high serum- and lipid-tolerence for the delivery of siRNA drugs to treat obesity and metabolic dysfunction
Biomaterials. 2022 Apr 28;285:121541. doi: 10.1016/j.biomaterials.2022.121541. Online ahead of print.ABSTRACTObesity is the major risk factor for metabolic diseases such as fatty liver, hyperlipidemia and insulin resistance. Beige fat has been recognized as a therapeutic target considering its great potential to burn energy. Since the evolutionary discovery of RNA interference and its utilization for gene knockdown in mammalian cells, a remarkable progress has been achieved in siRNA-based therapeutics. However, efficient delivery of siRNA into adipose tissues or differentiated adipocytes is challenging due to high lipid co...
Source: Biomaterials - May 9, 2022 Category: Materials Science Authors: Jin Qiu Qianqian Fan Sainan Xu Dongmei Wang Juntong Chen Sainan Wang Tianhui Hu Xinran Ma Yiyun Cheng Lingyan Xu Source Type: research

The mitochondrial protein PGAM5 suppresses energy consumption in brown adipocytes by repressing expression of uncoupling protein 1 Metabolism
Accumulating evidence suggests that brown adipose tissue (BAT) is a potential therapeutic target for managing obesity and related diseases. PGAM family member 5, mitochondrial serine/threonine protein phosphatase (PGAM5), is a protein phosphatase that resides in the mitochondria and regulates many biological processes, including cell death, mitophagy, and immune responses. Because BAT is a mitochondria-rich tissue, we have hypothesized that PGAM5 has a physiological function in BAT. We previously reported that PGAM5-knockout (KO) mice are resistant to severe metabolic stress. Importantly, lipid accumulation is suppressed i...
Source: Journal of Biological Chemistry - April 23, 2020 Category: Chemistry Authors: Sho Sugawara, Yusuke Kanamaru, Shiori Sekine, Lila Maekawa, Akinori Takahashi, Tadashi Yamamoto, Kengo Watanabe, Takao Fujisawa, Kazuki Hattori, Hidenori Ichijo Tags: Cell Biology Source Type: research

Myeloid-specific Asxl2 deletion limits diet-induced obesity by regulating energy expenditure
We previously established that global deletion of the enhancer of trithorax and polycomb (ETP) gene, Asxl2, prevents weight gain. Because proinflammatory macrophages recruited to adipose tissue are central to the metabolic complications of obesity, we explored the role of ASXL2 in myeloid lineage cells. Unexpectedly, mice without Asxl2 only in myeloid cells (Asxl2ΔLysM) were completely resistant to diet-induced weight gain and metabolically normal despite increased food intake, comparable activity, and equivalent fecal fat. Asxl2ΔLysM mice resisted HFD-induced adipose tissue macrophage infiltration and inflammatory cytok...
Source: Journal of Clinical Investigation - April 21, 2020 Category: Biomedical Science Authors: Wei Zou, Nidhi Rohatgi, Jonathan R. Brestoff, John R. Moley, Yongjia Li, Jesse W. Williams, Yael Alippe, Hua Pan, Terri A. Pietka, Gabriel Mbalaviele, Elizabeth P. Newberry, Nicholas O. Davidson, Anwesha Dey, Kooresh I. Shoghi, Richard D. Head, Samuel A. Source Type: research

RAMP2 influences glucagon receptor pharmacology via trafficking and signaling.
Abstract Endogenous satiety hormones provide an attractive target for obesity drugs. Glucagon causes weight loss by reducing food intake and increasing energy expenditure. To further understand the cellular mechanisms by which glucagon and related ligands activate the glucagon receptor (GCGR), we have investigated the interaction of the GCGR with RAMP2, a member of the family of Receptor Activity Modifying Proteins.We have used a combination of competition binding experiments, cell surface ELISA, functional assays assessing the Gαs and Gq pathways and β-arrestin recruitment, and siRNA knockdown to examine the ef...
Source: Endocrinology - June 6, 2017 Category: Endocrinology Authors: Cegla J, Jones BJ, Gardiner JV, Hodson DJ, Marjot T, McGlone ER, Tan TM, Bloom SR Tags: Endocrinology Source Type: research

Leptin Enhances ICAM-1 Expression, Induces Migration and Cytokine Synthesis, and Prolongs Survival of Human Airway Epithelial Cells.
Abstract There is rising interest in how obesity affects respiratory diseases, since epidemiological findings indicate a strong relationship between the two conditions. Leptin is a potent adipokine produced mainly by adipocytes. It regulates energy storage and expenditure and also induces inflammation. Previous studies have shown that leptin is able to activate inflammatory cells such as lymphocytes and granulocytes, but little is known about its effect on lung structural cells. The present study investigated the effects of leptin on human airway epithelial cells by using human primary airway epithelial cells and ...
Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - August 14, 2015 Category: Cytology Authors: Suzukawa M, Koketsu R, Baba S, Igarashi S, Nagase H, Yamaguchi M, Matsutani N, Kawamura M, Shoji S, Hebisawa A, Ohta K Tags: Am J Physiol Lung Cell Mol Physiol Source Type: research

De Novo Reconstruction of Adipose Tissue Transcriptomes Reveals Long Non-coding RNA Regulators of Brown Adipocyte Development.
Abstract Brown adipose tissue (BAT) protects against obesity by promoting energy expenditure via uncoupled respiration. To uncover BAT-specific long non-coding RNAs (lncRNAs), we used RNA-seq to reconstruct de novo transcriptomes of mouse brown, inguinal white, and epididymal white fat and identified ∼1,500 lncRNAs, including 127 BAT-restricted loci induced during differentiation and often targeted by key regulators PPARγ, C/EBPα, and C/EBPβ. One of them, lnc-BATE1, is required for establishment and maintenance of BAT identity and thermogenic capacity. lnc-BATE1 inhibition impairs concurrent activation of bro...
Source: Cell Metabolism - April 21, 2015 Category: Cytology Authors: Alvarez-Dominguez JR, Bai Z, Xu D, Yuan B, Lo KA, Yoon MJ, Lim YC, Knoll M, Slavov N, Chen S, Peng C, Lodish HF, Sun L Tags: Cell Metab Source Type: research

SMAD3 Suppresses FNDC5 and PGC-1{alpha} in Skeletal Muscle Signal Transduction
Beige adipose cells are a distinct and inducible type of thermogenic fat cell that express the mitochondrial uncoupling protein-1 and thus represent a powerful target for treating obesity. Mice lacking the TGF-β effector protein SMAD3 are protected against diet-induced obesity because of browning of their white adipose tissue (WAT), leading to increased whole body energy expenditure. However, the role SMAD3 plays in WAT browning is not clearly understood. Irisin is an exercise-induced skeletal muscle hormone that induces WAT browning similar to that observed in SMAD3-deficient mice. Together, these observations suggested ...
Source: Journal of Biological Chemistry - March 20, 2015 Category: Chemistry Authors: Tiano, J. P., Springer, D. A., Rane, S. G. Tags: Cell Biology Source Type: research

IKK epsilon is key to induction of insulin resistance in the hypothalamus and its inhibition reverses obesity.
Abstract IKK epsilon (IKKε) is induced by the activation of NFκB. Whole body IKKε knockout mice on a high fat diet (HFD) were protected from insulin resistance and showed altered energy balance. Here, we demonstrate that IKKε is expressed in neurons and is upregulated in the hypothalamus of obese mice, contributing to insulin and leptin resistance. Blocking IKKε in the hypothalamus of obese mice, using CAYMAN10576 or siRNA, decreased NFκB activation in this tissue, relieving the inflammatory environment. Inhibition of IKKε activity, but not TBK1, reduced IRS-1(Ser) phosphorylation and insulin and leptin res...
Source: Diabetes - May 8, 2014 Category: Endocrinology Authors: Weissmann L, Quaresma PG, Santos AC, de Matos AH, D'Ávila Bittencourt Pascoal V, Zanotto TM, Castro G, Guadgnini D, Martins da Silva J, Velloso LA, Bittencourt JC, Lopes-Cendes I, Saad MJ, Prada PO Tags: Diabetes Source Type: research