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Montréal, Canada

Mori H.,University of Michigan | Prestwich T.C.,University of Michigan | Reid M.A.,University of Michigan | Longo K.A.,Proteostasis Therapeutics | And 6 more authors.
Journal of Clinical Investigation | Year: 2012

Preadipocytes secrete several WNT family proteins that act through autocrine/paracrine mechanisms to inhibit adipogenesis. The activity of WNT ligands is often decreased by secreted frizzled-related proteins (SFRPs). Sfrp5 is strongly induced during adipocyte differentiation and increases in adipocytes during obesity, presumably to counteract WNT signaling. We tested the hypothesis that obesity-induced Sfrp5 expression promotes the development of new adipocytes by inhibiting endogenous suppressors of adipogenesis. As predicted, mice that lack functional SFRP5 were resistant to diet-induced obesity. However, counter to our hypothesis, we found that adipose tissue of SFRP5-deficient mice had similar numbers of adipocytes, but a reduction in large adipocytes. Transplantation of adipose tissue from SFRP5-deficient mice into leptin receptor-deficient mice indicated that the effects of SFRP5 deficiency are tissue-autonomous. Mitochondrial gene expression was increased in adipose tissue and cultured adipocytes from SFRP5-deficient mice. In adipocytes, lack of SFRP5 stimulated oxidative capacity through increased mitochondrial activity, which was mediated in part by PGC1α and mitochondrial transcription factor A. WNT3a also increased oxygen consumption and the expression of mitochondrial genes. Thus, our findings support a model of adipogenesis in which SFRP5 inhibits WNT signaling to suppress oxidative metabolism and stimulate adipocyte growth during obesity. Source

Gerin I.,University of Michigan | Gerin I.,Catholic University of Louvain | Bommer G.T.,University of Michigan | Bommer G.T.,Catholic University of Louvain | And 4 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2010

In this study, we explored the roles of microRNAs in adipocyte differentiation and metabolism. We first knocked down Argonaute2 (Ago2), a key enzyme in the processing of micro-RNAs (miRNAs), to investigate a potential role for miRNAs in adipocyte differentiation and/or metabolism. Although we did not observe dramatic differences in adipogenesis between Ago2 knock-down and control 3T3-L1 cells, incorporation of [14C]glucose or acetate into triacylglycerol, and steady-state levels of triacyglycerol were all reduced, suggesting a role for miRNAs in adipocyte metabolism. To study roles of specific miRNAs in adipocyte biology, we screened for miRNAs that are differentially expressed between preadipocytes and adipocytes for the 3T3-L1 and ST2 cell lines. Distinct subsets of miRNAs decline or increase during adipocyte conversion, whereas most miRNAs are not regulated. One locus encoding two miRNAs, 378/378*, contained within the intron of PGC-1β is highly induced during adipogenesis. When overexpressed in ST2 mesenchymal precursor cells, miRNA378/378* increases the size of lipid droplets and incorporation of [14C]acetate into triacylglycerol. Although protein and mRNA expression levels of C/EBPα, C/EBPβ, C/EBPδ, and PPARγ1 are unchanged, microarray and quantitative RT-PCR analyses indicate that a set of lipogenic genes are upregulated, perhaps due to increased expression of PPARγ2. Knockdown of miRNA378 and/or miRNA378* decreases accumulation of triacylglycerol. Interestingly, we made the unexpected finding that miRNA378/378* specifically increases transcriptional activity of C/EBPα and C/EBPβ on adipocyte gene promoters. Copyright © 2010 the American Physiological Society. Source

Yaden B.,Musculoskeletal Research | Yaden B.,Indiana University - Purdue University Indianapolis | Yaden B.,Eli Lilly and Company | Krishnan V.,Musculoskeletal Research | And 2 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2013

Human follistatin is a regulatory glycoprotein with widespread biologic functions, including antiinflammatory activities, woundhealing properties, and muscle-stimulating effects. The role of follistatin in a wide range of biologic activities shows promise for potential clinical application, which has prompted considerable interest in the investigation of the protein as a potential diseasemodifying agent. In spite of this potential, the development of follistatin as a broad use biotherapeutic has been severely hindered by a poor understanding and characterization of its pharmacokinetic/pharmacodynamic (PK/PD) relationships.Therefore, to better define these relationships, we performed in-depth analyses of the PK/PD relationships of native follistatin-315 (FST315). Our data indicate that the intrinsic PK/PD properties of native FST315 are poorly suited for acting as a parentally administered biotherapeutic with broad systemic effects. Here, we leveraged protein engineering to modify the PK characteristics of the native molecule by fusing FST315 to a murine IgG1 Fc and removing the intrinsic heparan sulfate-binding activity of follistatin. The engineered variant molecule had ̃100- and ̃1600-fold improvements in terminal half-life and exposure, respectively. In contrast to the native FST315, the variant showed a robust, dose-dependent pharmacological effect when administered subcutaneously on a weekly basis in mouse models of muscle atrophy and degeneration. These studies highlight the underappreciated and critical relationship between optimizing multiple physical and chemical properties of follistatin on its overall PK/PD profile. Moreover, our findings provide the first documented strategy toward the development of a follistatin therapeutic with potential use in patients affected with skeletal muscle diseases. © 2013 by The American Society for Pharmacology and Experimental Therapeutics. Source

Saito M.,Jikei University School of Medicine | Grynpas M.D.,Samuel Lunenfeld Research Institute | Burr D.B.,Indiana University | Allen M.R.,Indiana University | And 7 more authors.
Bone | Year: 2014

Eldecalcitol (ELD), an active form of vitamin D analog approved for the treatment of osteoporosis in Japan, increases lumbar spine bone mineral density (BMD), suppresses bone turnover markers, and reduces fracture risk in patients with osteoporosis. We have previously reported that treatment with ELD for 6. months improved the mechanical properties of the lumbar spine in ovariectomized (OVX) cynomolgus monkeys. ELD treatment increased lumbar BMD, suppressed bone turnover markers, and reduced histomorphometric parameters of both bone formation and resorption in vertebral trabecular bone. In this study, we elucidated the effects of ELD on bone quality (namely, mineralization, microarchitecture, microdamage, and bone collagen crosslinks) in OVX cynomolgus monkeys in comparison with OVX-vehicle control monkeys. Density fractionation of bone powder prepared from lumbar vertebrae revealed that ELD treatment shifted the distribution profile of bone mineralization to a higher density, and backscattered electron microscopic imaging showed improved trabecular bone connectivity in the ELD-treated groups. Higher doses of ELD more significantly reduced the amount of microdamage compared to OVX-vehicle controls. The fractionated bone powder samples were divided according to their density, and analyzed for collagen crosslinks. Enzymatic crosslinks were higher in both the high-density (≥. 2.0. mg/mL) and low-density (<. 2.0. mg/mL) fractions from the ELD-treated groups than in the corresponding fractions in the OVX-vehicle control groups. On the other hand, non-enzymatic crosslinks were lower in both the high- and low-density fractions. These observations indicated that ELD treatment stimulated the enzymatic reaction of collagen crosslinks and bone mineralization, but prevented non-enzymatic reaction of collagen crosslinks and accumulation of bone microdamage. Bone anti-resorptive agents such as bisphosphonates slow down bone remodeling so that bone mineralization, bone microdamage, and non-enzymatic collagen crosslinks all increase. Bone anabolic agents such as parathyroid hormone decrease bone mineralization and bone microdamage by stimulating bone remodeling. ELD did not fit into either category. Histological analysis indicated that the ELD treatment strongly suppressed bone resorption by reducing the number of osteoclasts, while also stimulating focal bone formation without prior bone resorption (bone minimodeling). These bidirectional activities of ELD may account for its unique effects on bone quality. © 2014. Source

Parlee S.D.,University of Michigan | Simon B.R.,University of Michigan | Scheller E.L.,University of Michigan | Alejandro E.U.,University of Michigan | And 4 more authors.
Endocrinology | Year: 2014

Nutritional or pharmacological perturbations during perinatal growth can cause persistent effects on the function of white adipose tissue, altering susceptibility to obesity later in life. Previous studies have established that saccharin, a nonnutritive sweetener, inhibits lipolysis in mature adipocytes and stimulates adipogenesis. Thus, the current study tested whether neonatal exposure to saccharin via maternal lactation increased susceptibility of mice to diet-induced obesity. Saccharin decreased body weight of female mice beginning postnatal week 3. Decreased liver weights on week 14 corroborated this diminished body weight. Initially, saccharin also reduced male mouse body weight. By week 5, weights transiently rebounded above controls, and by week 14, male body weights did not differ. Body composition analysis revealed that saccharin increased lean and decreased fat mass of male mice, the latter due to decreased adipocyte size and epididymal, perirenal, and sc adipose weights. A mild improvement in glucose tolerance without a change in insulin sensitivity or secretion aligned with this leaner phenotype. Interestingly, microcomputed tomography analysis indicated that saccharin also increased cortical and trabecular bone mass of male mice and modified cortical bone alone in female mice. A modest increase in circulating testosterone may contribute to the leaner phenotype in male mice. Accordingly, the current study established a developmental period in which saccharin at high concentrations reduces adiposity and increases lean and bone mass in male mice while decreasing generalized growth in female mice. Copyright © 2014 by the Endocrine Society. Source

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