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Overweight in Mice and Enhanced Adipogenesis in Vitro Are Associated with Lack of the Hedgehog Coreceptor Boc

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Overweight in Mice and Enhanced Adipogenesis in Vitro Are Associated with Lack of the Hedgehog Coreceptor Boc 2092 Diabetes Volume 64, June 2015 Hye-Jin Lee,1 Shin-Bum Jo,1 Anthony I. Romer,2,3 Hyo-Jeong Lim,1 Min-Jung Kim,4 Seung-Hoi Koo,4 Robert S. Krauss,2,3 and Jong-Sun Kang1 Overweight in Mice and Enhanced Adipogenesis In Vitro Are Associated With Lack of the Hedgehog Coreceptor Boc Diabetes 2015;64:2092–2103 | DOI: 10.2337/db14-1017 Obesity arises from a combination of genetic, environ- environmental, and behavioral factors that influence en- mental, and behavioral factors. However, the processes ergy balance. The principal feature of obesity is excessive that regulate white adipose tissue (WAT) expansion at accumulation of white adipose tissue (WAT) (1,3–5). Al- the level of the adipocyte are not well understood. The though obesity is understood to be a centrally regulated Hedgehog (HH) pathway plays a conserved role in consequence of overnutrition and/or reduced expenditure adipogenesis, inhibiting fat formation in vivo and in vitro, of energy, the processes that regulate WAT expansion at but it has not been shown that mice with reduced HH the level of the adipocyte are not well characterized. pathway activity have enhanced adiposity. We report WAT expansion occurs through adipocyte hypertrophy that mice lacking the HH coreceptor BOC displayed and hyperplasia, so such processes presumably engage at age-related overweight and excess WAT. They also some level the process of adipogenesis (3,4). Adipogenesis displayed alterations in some metabolic parameters has been analyzed with preadipocyte cell lines such as but normal food intake. Furthermore, they had an 3T3-L1 and various mutant mouse lines (6). These studies exacerbated response to a high-fat diet, including OBESITY STUDIES enhanced weight gain and adipocyte hypertrophy, livers elucidated a transcriptional network centered around with greater fat accumulation, and elevated expression PPARg and C/EBP family members, which drive differen- of genes related to adipogenesis, lipid metabolism, and tiation of preadipocytes into lipid-accumulating adipo- 2/2 fi adipokine production. Cultured Boc mouse embryo cytes (6). Recent studies have identi ed cells in the fibroblasts showed enhanced adipogenesis relative to stromal vascular fraction (SVF) of WAT that are bona Boc+/+ cells, and they expressed reduced levels of HH fide adipocyte progenitor cells (7,8). Such cells in WAT pathway target genes. Therefore, a loss-of-function must respond to hormonal and local cues that regulate mutation in an HH pathway component is associated homeostatic maintenance of this tissue. The cues that act with WAT accumulation and overweight in mice. Variant on adipocyte progenitor cells are not well understood, but alleles of such HH regulators may contribute to WAT among those implicated is the Hedgehog (HH) signaling accumulation in human individuals with additional pathway. genetic or lifestyle-based predisposition to obesity. HH proteins regulate developmental events in organ- isms as diverse as insects and mammals. Among mam- malian HH proteins, Sonic Hedgehog (SHH) plays the The prevalence of obesity and associated metabolic broadest role and is involved in the growth and/or pathologies has attracted attention to the identification morphogenesis of many body structures (9). HH proteins of etiological factors (1,2). Obesity arises from genetic, activate a conserved signal transduction pathway (10–12). 1Department of Molecular Cell Biology, Sungkyunkwan University School of Corresponding authors: Jong-Sun Kang, [email protected], and Robert S. Medicine, Samsung Biomedical Research Institute, Suwon, Republic of Korea Krauss, [email protected]. 2 Department of Developmental and Regenerative Biology, Icahn School of Received 1 July 2014 and accepted 1 January 2015. Medicine at Mount Sinai, New York, NY H.-J.L. and S.-B.J. contributed equally to this work. 3Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY © 2015 by the American Diabetes Association. Readers may use this article as 4Division of Life Sciences, Korea University, Seoul, Republic of Korea long as the work is properly cited, the use is educational and not for profit, and the work is not altered. diabetes.diabetesjournals.org Lee and Associates 2093 In the absence of ligand, the primary HH receptor RESEARCH DESIGN AND METHODS PTCH1 functions to inhibit signaling by a second mem- Mice braneprotein,SMO.BindingofHHtoPTCH1relieves BocAP-1 mice (19) were backcrossed onto a C57BL/6N back- inhibition of SMO, and SMO signals to activate path- ground for at least six generations. For age-related effects, 2 2 way target genes via GLI transcription factors. Among male Boc+/+ or Boc / mice backcrossed for six generations such target genes are Gli1 and Ptch1 themselves, and were used and weighed every 4 weeks over 32 weeks. To they are often used as readouts of pathway activity assess food intake, food was weighed and replenished – (10 12). every other day for individually caged mice for 2 weeks. 2 2 CDO (also called CDON), BOC, and GAS1 are cell For HFD-induced effects, male Boc+/+ or Boc / mice back- surface proteins that promote HH pathway activity as crossed for 10 generations were used. Four-week-old mice – ligand-binding coreceptors with PTCH1 (13 20). CDO were fed with HFD (60% fat content; Harlan) and weighed and BOC are related transmembrane proteins (21,22), weekly over 8 weeks. For blood glucose levels, tail vein whereas GAS1 is a GPI-anchored protein unrelated blood was used after animals were fasted for 16 h, with to CDO and BOC (23). Analysis of mice with targeted free access to water. For the glucose tolerance test (GTT), mutations in Cdon, Boc,andGas1 revealed that al- mice were fasted for 16 h and injected intraperitone- though none is essential for HH pathway activity, ally with 1.5 g 20% D-glucose/kg body weight (Sigma- they are collectively required for pathway function in Aldrich), followed by measurement of blood glucose levels. the early mouse embryo (13,14,16,19). A ternary com- For the insulin tolerance test (ITT), mice were fasted for plex of HH ligand, PTCH1, and at least one of these 6 h and injected intraperitoneally with 1 IU insulin/kg coreceptors appears to be required for successful sig- body weight (Sigma-Aldrich), followed by measurement nal transduction (15,16,24). Boc-null mice, the subject of glucose levels. Mouse tissues were immediately frozen of this study, are viable and fertile but display defects in liquid nitrogen and stored at 270°C or fixed in 4% in SHH-dependent neural patterning and axon guidance paraformaldehyde (PFA). Plasma insulin was measured – (19,25 28). with the Mouse Insulin ELISA Kit (U-type; Shibayagi The HH pathway negatively regulates adipogenesis. Corp.), and serum triglycerides and nonesterified fatty Activation of the HH pathway with either SHH or the acids were measured by colorimetric assay kits (Wako). SMO agonist purmorphamine inhibited adipogenesis of For assessment of metabolic parameters (Fig. 2), – +/+ 2/2 3T3-L1 and additional cell lines (29 32). Furthermore, 5-month-old Boc and Boc mice were analyzed with blockade of HH signaling, with a dominant-negativeform metabolic cages (Harvard Apparatus; Panlab). Measure- of GLI2 or the SMO antagonist cyclopamine, en- ments were performed for 48 h, during which animals hanced adipogenesis of these cells in response to had access to food and water. Core body temperature inducing factors (31,32). HH signals blocked early was measured with an HB-101 homeothermic blanket/ steps of adipogenesis, upstream of the expression of pad equipment (Harvard Apparatus). PPARg (29,31,32). These studies suggest that the HH pathway functions to block differentiation of preadipo- Histology, Oil Red O Staining, and Placental Alkaline Phosphatase Staining cytes in vitro. Experiments in mice are consistent with For hematoxylin-eosin (H-E) staining, WAT and liver tissues this notion. Adult mice homozygous for a hypomorphic were fixedandprocessedfor20-mm paraffinsections.For allele of Ptch1 showed reduced WAT mass, which had Oil Red O staining, livers were fixed in 4% PFA and dehy- lower levels of adipose markers and elevated levels of drated by sucrose gradient followed by an optimal cutting HH target genes (33). Adipose tissue–specific mutation temperature compound-cryosection (10 mm)andOilRedO of another HH pathway inhibitor, Sufu, led to a loss of staining. For Oil Red O staining of differentiated mouse WAT (34). Finally, mice with diet-induced or genetic embryonic fibroblasts (MEFs) and 3T3-L1 cells, cultures (ob/ob) obesity displayed decreased expression of HH were fixed in 10% formaldehyde for 10 min and stained pathway components (31). with Oil Red O. Stained plates were treated with 1 mL Although mice with a genetic gain of function in HH isopropanol/4% NP-40 for 10 min by a gentle shaking, and pathway activity showed loss of WAT (33,34), it has not extracted Oil Red O was quantified by measuring optical been demonstrated that mice with a loss of HH activity density at 520 nm. For placental alkaline phosphatase have enhanced adiposity. We report that mice with (PLAP) staining, tissues were fixed with 2% PFA plus 0.2% agermlinemutationinBoc display age-dependent over- glutaraldehyde for 2 h at 4°C, washed in PBS, permeabilized weightduetoanincreaseinWAT.Thesemicealsoshow in 0.3% Triton overnight at 4°C, washed in saline, heat inac- an exaggerated response to a high-fat diet (HFD), and 2 2 tivated for 30 min at 72°C, washed in NTM (100 mmol/L Boc / embryo fibroblasts differentiate into adipocytes NaCl, 100 mmol/L Tris-HCl, pH 9.5, 50 mmol/L MgCl ) more efficiently than wild-type cells. These results re- 2 buffer, and stained with BM purple (Roche). veal that BOC, presumably acting as an SHH coreceptor, is required for maintenance of normal weight in vivo Cell Cultures and appropriate regulation of adipogenic differentiation Preparation of the SVF from WAT was performed as in vitro.
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