Browsing by Subject "Adipose"

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    Cilia Signaling and Obesity
    (Elsevier, 2021) Engle, Staci E.; Bansal, Ruchi; Antonellis, Patrick J.; Berbari, Nicolas F.; Biology, School of Science
    An emerging number of rare genetic disorders termed ciliopathies are associated with pediatric obesity. It is becoming clear that the mechanisms associated with cilia dysfunction and obesity in these syndromes are complex. In addition to ciliopathic syndromic forms of obesity, several cilia-associated signaling gene mutations also lead to morbid obesity. While cilia have critical and diverse functions in energy homeostasis including their roles in centrally mediated food intake as well as in peripheral tissues, many questions remain. Here, we briefly discuss the syndromic ciliopathies and monoallelic cilia signaling gene mutations associated with obesity. We also describe potential ways cilia may be involved in common obesity. We discuss how neuronal cilia impact food intake potentially through leptin signaling and changes in ciliary G protein-coupled receptor (GPCR) signaling. We highlight several recent studies that have implicated the potential for cilia in peripheral tissues such as adipose and the pancreas to contribute to metabolic dysfunction. Then we discuss the potential for cilia to impact energy homeostasis through their roles in both development and adult tissue homeostasis. The studies discussed in this review highlight how a comprehensive understanding of the requirement of cilia for the regulation of diverse biological functions will contribute to our understanding of common forms of obesity.
  • Thumbnail Image
    Item
    Coronary perivascular adipose tissue and vascular smooth muscle function: influence of obesity
    (2016-03-22) Noblet, Jillian Nicole; Tune, Johnathan D.
    Factors released from coronary perivascular adipose tissue (PVAT), which surrounds large coronary arteries, have been implicated in the development of coronary disease. However, the precise contribution of coronary PVAT-derived factors to the initiation and progression of coronary vascular dysfunction remains ill defined. Accordingly, this investigation was designed to delineate the mechanisms by which PVAT-derived factors influence obesity-induced coronary smooth muscle dysfunction. Isometric tension studies of coronary arteries from lean and obese swine demonstrated that both lean and obese coronary PVAT attenuate vasodilation via inhibitory effects on smooth muscle K+ channels. Specifically, lean coronary PVAT attenuated KCa and KV7 channel-mediated dilation, whereas obese coronary PVAT impaired KATP channel-mediated dilation. Importantly, these effects were independent of alterations in underlying smooth muscle function in obese arteries. The PVAT-derived factor calpastatin impaired adenosine dilation in lean but not obese arteries, suggesting that alterations in specific factors may contribute to the development of smooth muscle dysfunction. Further studies tested the hypothesis that leptin, which is expressed in coronary PVAT and is upregulated in obesity, acts as an upstream mediator of coronary smooth muscle dysfunction. Long-term administration (3 day culture) of obese concentrations of leptin markedly altered the coronary artery proteome, favoring pathways associated with calcium signaling and cellular proliferation. Isometric tension studies demonstrated that short-term (30 min) exposure to leptin potentiated depolarization-induced contraction of coronary arteries and that this effect was augmented following longer-term leptin administration (3 days). Inhibition of Rho kinase reduced leptin-mediated increases in coronary artery contractions. Acute treatment was associated with increased Rho kinase activity, whereas longer-term exposure was associated with increases in Rho kinase protein abundance. Alterations in Rho kinase signaling were also associated with leptin-mediated increases in coronary vascular smooth muscle proliferation. These findings provide novel mechanistic evidence linking coronary PVAT with vascular dysfunction and further support a role for coronary PVAT in the pathogenesis of coronary disease.
  • Thumbnail Image
    Item
    Piceatannol, a Dietary Polyphenol, Alleviates Adipose Tissue Loss in Pre-Clinical Model of Cancer-Associated Cachexia via Lipolysis Inhibition
    (MDPI, 2022-05-31) Kershaw, Jonathan C.; Elzey, Bennett D.; Guo, Xiao-Xuan; Kim, Kee-Hong; Urology, School of Medicine
    Cancer-associated cachexia (CAC) is the nutrition-independent loss of lean muscle and adipose tissues, and results in reduced chemotherapy effectiveness and increased mortality. Preventing adipose loss is considered a key target in the early stages of cachexia. Lipolysis is considered the central driver of adipose loss in CAC. We recently found that piceatannol, but not its analogue resveratrol, exhibits an inhibitory effect on lipolysis. The objective of this study was to investigate the role of piceatannol in cancer-associated lipolysis and cachexia-induced weight loss. Cancer cell-induced lipolysis in adipocytes was stimulated using cancer-conditioned media (CCM) or co-culture with human pancreatic cancer cells and the cachexia-associated cytokines TNF-α and interleukin-6 in 3T3-L1 adipocytes. C26 colon carcinoma-bearing mice were modeled using CAC in vivo. Piceatannol reduced cancer-associated lipolysis by at least 50% in both CCM and cytokine-induced lipolysis in vitro. Further gene and protein analysis confirmed that piceatannol modulated the stability of lipolytic proteins. Moreover, piceatannol protected tumor-bearing mice against weight-loss in early stages of CAC largely through preserving adipose tissue, with no effect on survival. This study demonstrates the use of a dietary compound to preserve adipose in models of early stage CAC and provides groundwork for further investigation of piceatannol or piceatannol-rich foods as alternative medicine in the preservation of body fat mass and future CAC therapy.
  • Thumbnail Image
    Item
    Profiling of Adipose and Skeletal Muscle in Human Pancreatic Cancer Cachexia Reveals Distinct Gene Profiles with Convergent Pathways
    (MDPI, 2021-04-20) Narasimhan, Ashok; Zhong, Xiaoling; Au, Ernie P.; Ceppa, Eugene P.; Nakeeb, Atilla; House, Michael G.; Zyromski, Nicholas J.; Schmidt, C. Max; Schloss, Katheryn N. H.; Schloss, Daniel E. I.; Liu, Yunlong; Jiang, Guanglong; Hancock, Bradley A.; Radovich, Milan; Kays, Joshua K.; Shahda, Safi; Couch, Marion E.; Koniaris, Leonidas G.; Zimmers, Teresa A.; Surgery, School of Medicine
    The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditions (n = 11) and patients with PDAC (n = 24). Self-reported weight loss and body composition measurements defined cachexia status. Gene profiling was done using ion proton sequencing. Results were queried against external datasets for validation. 961 DE genes were identified from muscle and 2000 from adipose tissue, demonstrating greater response of adipose than muscle. In addition to known cachexia genes such as FOXO1, novel genes from muscle, including PPP1R8 and AEN correlated with cancer weight loss. All the adipose correlated genes including SCGN and EDR17 are novel for PDAC cachexia. Pathway analysis demonstrated shared pathways but largely non-overlapping genes in both tissues. Age related muscle loss predominantly had a distinct gene profiles compared to cachexia. This analysis of matched, externally validate gene expression points to novel targets in cachexia.
  • Thumbnail Image
    Item
    Tumor, Fat and Skeletal Muscle Crosstalk via IL-6R Trans-Signaling Mediates Pancreatic Cancer Cachexia
    (2020-10) Rupert, Joseph Emil; Zimmers, Teresa A.; Broxmeyer, Hal E.; Goebl, Mark G.; O'Connell, Thomas M.; Quilliam, Lawrence A.
    Cachexia, the involuntary loss of fat and muscle is associated with pancreatic ductal adenocarcinoma (PDAC), contributing to its 90% 5-year mortality rate. Elevated Interleukin-6 (IL-6) expression is associated with cachexia severity and reduced survival in patients. IL-6 in cancer is well documented, but IL-6 signaling crosstalk among tissues is not. IL-6 signals by binding membrane-bound IL-6 receptor (IL-6R) (classical signaling) or soluble IL- 6R (sIL6R; trans-signaling) produced by shedding of the membrane receptor primarily from muscle, liver and leukocytes. Herein I investigate the role of tumorderived IL-6 on muscle and fat crosstalk in PDAC. Loss of IL-6 expression in murine KPC PDAC cells was accomplished by CRISPR/Cas9 mutagenesis of the Il6 gene. Orthotopic KPC IL-6 knockout (KPC-IL-6KO) tumor-bearing mice had reduced cachexia, with attenuated fat loss and no significant muscle loss, and longer survival versus KPC controls. Only KPC tumor-bearing mice had significant myosteatosis, aberrant branched chain amino acid and fatty acid metabolism, and reduced pyruvate entry into the TCA-cycle, determined by increased pyruvate dehydrogenase kinase 4 (PDK4) expression in muscle. Muscle was a main source of sIL6R, and fat a primary contributor of IL-6 in KPC tumor-bearing mice. Myosteatosis leads to activation of lipid-sensitive kinases like protein kinase C theta (PKCθ, gene name Prkcq) in muscle. KPC tumorbearing mice had increased muscle PKCθ activation, and PKCθ is known to regulate metabolism and inflammation. Prkcq-/- KPC tumor-bearing mice had reduced cachexia and maintained muscle mass and force production versus wild type tumor-bearing mice. Together these data implicate progressive signaling mechanisms whereby tumor-derived IL-6 is associated with increased muscle IL6R expression and fat lipolysis, promoting myosteatosis and muscle PKCθ activation, ultimately increasing cachexia severity in PDAC.