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Endocrinology

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Paracrine regulation of fat cell formation in bone marrow cultures via adiponectin and prostaglandins
Takafumi Yokota, … , Yuji Matsuzawa, Paul W. Kincade
Takafumi Yokota, … , Yuji Matsuzawa, Paul W. Kincade
Published May 15, 2002
Citation Information: J Clin Invest. 2002;109(10):1303-1310. https://doi.org/10.1172/JCI14506.
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Paracrine regulation of fat cell formation in bone marrow cultures via adiponectin and prostaglandins

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Abstract

Adiponectin, an adipocyte-derived hormone, was recently shown to have potential therapeutic applications in diabetes and obesity because of its influence on glucose and lipid metabolism. We found that brown fat in normal human bone marrow contains this protein and used marrow-derived preadipocyte lines and long-term cultures to explore potential roles in hematopoiesis. Recombinant adiponectin blocked fat cell formation in long-term bone marrow cultures and inhibited the differentiation of cloned stromal preadipocytes. Adiponectin also caused elevated expression of cyclooxygenase-2 (COX-2) by these stromal cells and induced release of prostaglandin E2 (PGE2). The COX-2 inhibitor Dup-697 prevented the inhibitory action of adiponectin on preadipocyte differentiation, suggesting involvement of stromal cell–derived prostanoids. Furthermore, adiponectin failed to block fat cell generation when bone marrow cells were derived from B6,129SPtgs2tm1Jed (COX-2+/–) mice. These observations show that preadipocytes represent direct targets for adiponectin action, establishing a paracrine negative feedback loop for fat regulation. They also link adiponectin to the COX-2–dependent PGs that are critical in this process.

Authors

Takafumi Yokota, C.S. Reddy Meka, Kay L. Medina, Hideya Igarashi, Phillip C. Comp, Masahiko Takahashi, Makoto Nishida, Kenji Oritani, Jun-ichiro Miyagawa, Tohru Funahashi, Yoshiaki Tomiyama, Yuji Matsuzawa, Paul W. Kincade

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Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes
Ripudaman S. Hundal, … , Steven E. Shoelson, Gerald I. Shulman
Ripudaman S. Hundal, … , Steven E. Shoelson, Gerald I. Shulman
Published May 15, 2002
Citation Information: J Clin Invest. 2002;109(10):1321-1326. https://doi.org/10.1172/JCI14955.
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Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes

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Abstract

Recent studies have implicated fatty acid-dependent activation of the serine kinase IKKβ, which plays a key role in tissue inflammation, in the pathogenesis of insulin resistance. High doses of salicylates have recently been shown to inhibit IKKβ activity and might therefore ameliorate insulin resistance and improve glucose tolerance in patients with type 2 diabetes. To test this hypothesis, we studied nine type 2 diabetic subjects before and after 2 weeks of treatment with aspirin (∼7 g/d). Subjects underwent mixed-meal tolerance tests and hyperinsulinemic-euglycemic clamps with [6,6-2H2]glucose to assess glucose turnover before and after treatment. High-dose aspirin treatment resulted in a ∼25% reduction in fasting plasma glucose, associated with a ∼15% reduction in total cholesterol and C-reactive protein, a ∼50% reduction in triglycerides, and a ∼30% reduction in insulin clearance, despite no change in body weight. During a mixed-meal tolerance test, the areas under the curve for plasma glucose and fatty acid levels decreased by ∼20% and ∼50%, respectively. Aspirin treatment also resulted in a ∼20% reduction in basal rates of hepatic glucose production and a ∼20% improvement in insulin-stimulated peripheral glucose uptake under matched plasma insulin concentrations during the clamp. In conclusion, these data support the hypothesis that IKKβ represents a new target for treating type 2 diabetes mellitus.

Authors

Ripudaman S. Hundal, Kitt F. Petersen, Adam B. Mayerson, Pritpal S. Randhawa, Silvio Inzucchi, Steven E. Shoelson, Gerald I. Shulman

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Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy
Kitt Falk Petersen, … , Phillip Gorden, Gerald I. Shulman
Kitt Falk Petersen, … , Phillip Gorden, Gerald I. Shulman
Published May 15, 2002
Citation Information: J Clin Invest. 2002;109(10):1345-1350. https://doi.org/10.1172/JCI15001.
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Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy

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Abstract

Lipodystrophy is a rare disorder that is characterized by selective loss of subcutaneous and visceral fat and is associated with hypertriglyceridemia, hepatomegaly, and disordered glucose metabolism. It has recently been shown that chronic leptin treatment ameliorates these abnormalities. Here we show that chronic leptin treatment improves insulin-stimulated hepatic and peripheral glucose metabolism in severely insulin-resistant lipodystrophic patients. This improvement in insulin action was associated with a marked reduction in hepatic and muscle triglyceride content. These data suggest that leptin may represent an important new therapy to reverse the severe hepatic and muscle insulin resistance and associated hepatic steatosis in patients with lipodystrophy.

Authors

Kitt Falk Petersen, Elif Arioglu Oral, Sylvie Dufour, Douglas Befroy, Charlotte Ariyan, Chunli Yu, Gary W. Cline, Alex M. DePaoli, Simeon I. Taylor, Phillip Gorden, Gerald I. Shulman

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Anabolic effects of a G protein–coupled receptor kinase inhibitor expressed in osteoblasts
Robert F. Spurney, … , Farshid Guilak, L. Darryl Quarles
Robert F. Spurney, … , Farshid Guilak, L. Darryl Quarles
Published May 15, 2002
Citation Information: J Clin Invest. 2002;109(10):1361-1371. https://doi.org/10.1172/JCI14663.
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Anabolic effects of a G protein–coupled receptor kinase inhibitor expressed in osteoblasts

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Abstract

G protein–coupled receptors (GPCRs) play a key role in regulating bone remodeling. Whether GPCRs exert anabolic or catabolic osseous effects may be determined by the rate of receptor desensitization in osteoblasts. Receptor desensitization is largely mediated by direct phosphorylation of GPCR proteins by a family of enzymes termed GPCR kinases (GRKs). We have selectively manipulated GRK activity in osteoblasts in vitro and in vivo by overexpressing a GRK inhibitor. We found that expression of a GRK inhibitor enhanced parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor-stimulated cAMP generation and inhibited agonist-induced phosphorylation of this receptor in cell culture systems, consistent with attenuation of receptor desensitization. To determine the effect of GRK inhibition on bone formation in vivo, we targeted the expression of a GRK inhibitor to mature osteoblasts using the mouse osteocalcin gene 2 (OG2) promoter. Transgenic mice demonstrated enhanced bone remodeling as well as enhanced urinary excretion of the osteoclastic activity marker dexoypyridinoline. Both osteoprotegrin and OPG ligand mRNA levels were altered in calvaria of transgenic mice in a pattern that would promote osteoclast activation. The predominant effect of the transgene, however, was anabolic, as evidenced by an increase in bone density and trabecular bone volume in the transgenic mice compared with nontransgenic littermate controls.

Authors

Robert F. Spurney, Patrick J. Flannery, Sanford C. Garner, Krairerk Athirakul, Shiguang Liu, Farshid Guilak, L. Darryl Quarles

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β cell expression of IGF-I leads to recovery from type 1 diabetes
Mónica George, … , Jean Christophe Devedjian, Fatima Bosch
Mónica George, … , Jean Christophe Devedjian, Fatima Bosch
Published May 1, 2002
Citation Information: J Clin Invest. 2002;109(9):1153-1163. https://doi.org/10.1172/JCI12969.
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β cell expression of IGF-I leads to recovery from type 1 diabetes

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Abstract

Patients with type 1 diabetes are identified after the onset of the disease, when β cell destruction is almost complete. β cell regeneration from islet cell precursors might reverse this disease, but factors that can induce β cell neogenesis and replication and prevent a new round of autoimmune destruction remain to be identified. Here we show that expression of IGF-I in β cells of transgenic mice (in both C57BL/6–SJL and CD-1 genetic backgrounds) counteracts cytotoxicity and insulitis after treatment with multiple low doses of streptozotocin (STZ). STZ-treated nontransgenic mice developed high hyperglycemia and hypoinsulinemia, lost body weight, and died. In contrast, STZ-treated C57BL/6–SJL transgenic mice showed mild hyperglycemia for about 1 month, after which they normalized glycemia and survived. After STZ treatment, all CD-1 mice developed high hyperglycemia, hypoinsulinemia, polydipsia, and polyphagia. However, STZ-treated CD-1 transgenic mice gradually normalized all metabolic parameters and survived. β cell mass increased in parallel as a result of neogenesis and β cell replication. Thus, our results indicate that local expression of IGF-I in β cells regenerates pancreatic islets and counteracts type 1 diabetes, suggesting that IGF-I gene transfer to the pancreas might be a suitable therapy for this disease.

Authors

Mónica George, Eduard Ayuso, Alba Casellas, Cristina Costa, Jean Christophe Devedjian, Fatima Bosch

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Parathyroid hormone is essential for normal fetal bone formation
Dengshun Miao, … , Andrew C. Karaplis, David Goltzman
Dengshun Miao, … , Andrew C. Karaplis, David Goltzman
Published May 1, 2002
Citation Information: J Clin Invest. 2002;109(9):1173-1182. https://doi.org/10.1172/JCI14817.
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Parathyroid hormone is essential for normal fetal bone formation

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Abstract

Parathyroid hormone (PTH) is a potent pharmacologic inducer of new bone formation, but no physiologic anabolic effect of PTH on adult bone has been described. We investigated the role of PTH in fetal skeletal development by comparing newborn mice lacking either PTH, PTH-related peptide (PTHrP), or both peptides. PTH-deficient mice were dysmorphic but viable, whereas mice lacking PTHrP died at birth with dyschondroplasia. PTH-deficient mice uniquely demonstrated diminished cartilage matrix mineralization, decreased neovascularization with reduced expression of angiopoietin-1, and reduced metaphyseal osteoblasts and trabecular bone. Compound mutants displayed the combined cartilaginous and osseous defects of both single mutants. These results indicate that coordinated action of both PTH and PTHrP are required to achieve normal fetal skeletal morphogenesis, and they demonstrate an essential function for PTH at the cartilage-bone interface. The effect of PTH on fetal osteoblasts may be relevant to its postnatal anabolic effects on trabecular bone.

Authors

Dengshun Miao, Bin He, Andrew C. Karaplis, David Goltzman

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Pdx1 restores β cell function in Irs2 knockout mice
Jake A. Kushner, … , Marc R. Montminy, Morris F. White
Jake A. Kushner, … , Marc R. Montminy, Morris F. White
Published May 1, 2002
Citation Information: J Clin Invest. 2002;109(9):1193-1201. https://doi.org/10.1172/JCI14439.
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Pdx1 restores β cell function in Irs2 knockout mice

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Abstract

The homeodomain transcription factor Pdx1 is required for pancreas development, including the differentiation and function of β cells. Mutations in Pdx1 or upstream hepatocyte nuclear factors cause autosomal forms of early-onset diabetes (maturity-onset diabetes of the young [MODY]). In mice, the Irs2 branch of the insulin/Igf signaling system mediates peripheral insulin action and pancreatic β cell growth and function. To investigate whether β cell failure in Irs2–/– mice might be related to dysfunction of MODY-related transcription factors, we measured the expression of Pdx1 in islets from young Irs2–/– mice. Before the onset of diabetes, Pdx1 was reduced in islets from Irs2–/– mice, whereas it was expressed normally in islets from wild-type or Irs1–/– mice, which do not develop diabetes. Whereas male Irs2–/–Pdx1+/+ mice developed diabetes between 8 and 10 weeks of age, haploinsufficiency for Pdx1 caused diabetes in newborn Irs2–/– mice. By contrast, transgenic expression of Pdx1 restored β cell mass and function in Irs2–/– mice and promoted glucose tolerance throughout life, as these mice survived for at least 20 months without diabetes. Our results suggest that dysregulation of Pdx1 might represent a common link between ordinary type 2 diabetes and MODY.

Authors

Jake A. Kushner, Jing Ye, Markus Schubert, Deborah J. Burks, Matthew A. Dow, Carrie L. Flint, Sanjoy Dutta, Christopher V.E. Wright, Marc R. Montminy, Morris F. White

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Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids
Robert S. Weinstein, … , A. Michael Parfitt, Stavros C. Manolagas
Robert S. Weinstein, … , A. Michael Parfitt, Stavros C. Manolagas
Published April 15, 2002
Citation Information: J Clin Invest. 2002;109(8):1041-1048. https://doi.org/10.1172/JCI14538.
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Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids

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Abstract

Glucocorticoids depress bone formation by inhibiting osteoblastogenesis and increasing osteoblast apoptosis. However, the role of bone resorption in the initial rapid phase of bone loss characteristic of glucocorticoid-induced osteoporosis is unexplained, and the reason for the efficacy of bisphosphonates in this condition remains unknown. We report that in murine osteoclast cultures, glucocorticoids prolonged the baseline survival of osteoclasts and antagonized bisphosphonate-induced caspase activation and apoptosis by a glucocorticoid receptor–mediated action. Consistent with the in vitro evidence, in a murine model of glucocorticoid-induced osteoporosis, the number of cancellous osteoclasts increased, even though osteoclast progenitor number was reduced. Moreover, in mice receiving both glucocorticoids and bisphosphonates, the expected proapoptotic effect of bisphosphonates on osteoclasts was abrogated, as evidenced by maintenance of osteoclast numbers and, additionally, loss of bone density. In contrast, bisphosphonate administration prevented glucocorticoid-induced osteoblast apoptosis. These results indicate that the early loss of bone with glucocorticoid excess is caused by extension of the life span of pre-existing osteoclasts, an effect not preventable by bisphosphonates. Therefore, the early beneficial effects of these agents must be due, in part, to prolonging the life span of osteoblasts.

Authors

Robert S. Weinstein, Jin-Ran Chen, Cara C. Powers, Scott A. Stewart, Reid D. Landes, Teresita Bellido, Robert L. Jilka, A. Michael Parfitt, Stavros C. Manolagas

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Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1
Hubert C. Chen, … , Robert H. Eckel, Robert V. Farese Jr.
Hubert C. Chen, … , Robert H. Eckel, Robert V. Farese Jr.
Published April 15, 2002
Citation Information: J Clin Invest. 2002;109(8):1049-1055. https://doi.org/10.1172/JCI14672.
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Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1

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Abstract

Acyl coenzyme A:diacylglycerol acyltransferase 1 (DGAT1) is one of two known DGAT enzymes that catalyze the final step in mammalian triglyceride synthesis. DGAT1-deficient mice are resistant to diet-induced obesity through a mechanism involving increased energy expenditure. Here we show that these mice have decreased levels of tissue triglycerides, as well as increased sensitivity to insulin and to leptin. Importantly, DGAT1 deficiency protects against insulin resistance and obesity in agouti yellow mice, a model of severe leptin resistance. In contrast, DGAT1 deficiency did not affect energy and glucose metabolism in leptin-deficient (ob/ob) mice, possibly due in part to a compensatory upregulation of DGAT2 expression in the absence of leptin. Our results suggest that inhibition of DGAT1 may be useful in treating insulin resistance and leptin resistance in human obesity.

Authors

Hubert C. Chen, Steven J. Smith, Zuleika Ladha, Dalan R. Jensen, Luis D. Ferreira, Leslie K. Pulawa, James G. McGuire, Robert E. Pitas, Robert H. Eckel, Robert V. Farese Jr.

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Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element
Thierry Claudel, … , Folkert Kuipers, Bart Staels
Thierry Claudel, … , Folkert Kuipers, Bart Staels
Published April 1, 2002
Citation Information: J Clin Invest. 2002;109(7):961-971. https://doi.org/10.1172/JCI14505.
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Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element

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Abstract

Serum levels of HDL are inversely correlated with the risk of coronary heart disease. The anti-atherogenic effect of HDL is partially mediated by its major protein constituent apoA-I. In this study, we identify bile acids that are activators of the nuclear receptor farnesoid X receptor (FXR) as negative regulators of human apoA-I expression. Intrahepatocellular accumulation of bile acids, as seen in patients with progressive familial intrahepatic cholestasis and biliary atresia, was associated with diminished apoA-I serum levels. In human apoA-I transgenic mice, treatment with the FXR agonist taurocholic acid strongly decreased serum concentrations and liver mRNA levels of human apoA-I, which was associated with reduced serum HDL levels. Incubation of human primary hepatocytes and hepatoblastoma HepG2 cells with bile acids resulted in a dose-dependent downregulation of apoA-I expression. Promoter mutation analysis and gel-shift experiments in HepG2 cells demonstrated that bile acid–activated FXR decreases human apoA-I promoter activity by a negative FXR response element mapped to the C site. FXR bound this site and repressed transcription in a manner independent of retinoid X receptor. The nonsteroidal synthetic FXR agonist GW4064 likewise decreased apoA-I mRNA levels and promoter activity in HepG2 cells.

Authors

Thierry Claudel, Ekkehard Sturm, Hélène Duez, Inés Pineda Torra, Audrey Sirvent, Vladimir Kosykh, Jean-Charles Fruchart, Jean Dallongeville, Dean W. Hum, Folkert Kuipers, Bart Staels

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Dynamin 2 prevents insulin granule traffic jams
Fan Fan and colleagues demonstrate that dynamin 2 is important for maintaining insulin secretion dynamics in β cells…
Published September 28, 2015
Scientific Show StopperEndocrinology
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UPR stress gets β cells going
Rohit Sharma and colleagues reveal that insulin demand-induced β cell proliferation is regulated by the unfolded protein response…
Published September 21, 2015
Scientific Show StopperEndocrinology
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Restricting β cell growth
Sung Hee Um and colleagues reveal that S6K1-dependent alterations of β cell size and function are independent of intrauterine growth restriction…
Published June 15, 2015
Scientific Show StopperEndocrinology
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Insight into Kallmann syndrome
Anna Cariboni and colleagues demonstrate that dysfunctional SEMA3E results in gonadotropin-releasing hormone neuron deficiency…
Published May 18, 2015
Scientific Show StopperEndocrinology
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L cells to the rescue
Natalia Peterson and colleagues demonstrate that increasing L cell populations in the gut improves insulin responses and glucose tolerance in a murine type 2 diabetes model…
Published December 15, 2014
Scientific Show StopperEndocrinology
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