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Dive into the research topics where Christoph Buettner is active.

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Featured researches published by Christoph Buettner.


Journal of Clinical Investigation | 2008

Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice

Douglas Osei-Hyiaman; Jie Liu; Liang Zhou; Grzegorz Godlewski; Judith Harvey-White; Won-Il Jeong; Sándor Bátkai; Giovanni Marsicano; Beat Lutz; Christoph Buettner; George Kunos

Diet-induced obesity is associated with fatty liver, insulin resistance, leptin resistance, and changes in plasma lipid profile. Endocannabinoids have been implicated in the development of these associated phenotypes, because mice deficient for the cannabinoid receptor CB1 (CB1-/-) do not display these changes in association with diet-induced obesity. The target tissues that mediate these effects, however, remain unknown. We therefore investigated the relative role of hepatic versus extrahepatic CB1 receptors in the metabolic consequences of a high-fat diet, using liver-specific CB1 knockout (LCB1-/-) mice. LCB1(-/-) mice fed a high-fat diet developed a similar degree of obesity as that of wild-type mice, but, similar to CB1(-/-) mice, had less steatosis, hyperglycemia, dyslipidemia, and insulin and leptin resistance than did wild-type mice fed a high-fat diet. CB1 agonist-induced increase in de novo hepatic lipogenesis and decrease in the activity of carnitine palmitoyltransferase-1 and total energy expenditure were absent in both CB1(-/-) and LCB1(-/-) mice. We conclude that endocannabinoid activation of hepatic CB1 receptors contributes to the diet-induced steatosis and associated hormonal and metabolic changes, but not to the increase in adiposity, observed with high-fat diet feeding. Theses studies suggest that peripheral CB1 receptors could be selectively targeted for the treatment of fatty liver, impaired glucose homeostasis, and dyslipidemia in order to minimize the neuropsychiatric side effects of nonselective CB1 blockade during treatment of obesity-associated conditions.


Nature Medicine | 2008

Leptin controls adipose tissue lipogenesis via central, STAT3–independent mechanisms

Christoph Buettner; Evan D. Muse; Andrew Cheng; Linghong Chen; Thomas Scherer; Alessandro Pocai; Kai Su; Bob Cheng; Xiasong Li; Judith Harvey-White; Gary J. Schwartz; George Kunos; Luciano Rossetti

Leptin (encoded by Lep) controls body weight by regulating food intake and fuel partitioning. Obesity is characterized by leptin resistance and increased endocannabinoid tone. Here we show that leptin infused into the mediobasal hypothalamus (MBH) of rats inhibits white adipose tissue (WAT) lipogenesis, which occurs independently of signal transducer and activator of transcription-3 (STAT3) signaling. Correspondingly, transgenic inactivation of STAT3 signaling by mutation of the leptin receptor (s/s mice) leads to reduced adipose mass compared to db/db mice (complete abrogation of leptin receptor signaling). Conversely, the ability of hypothalamic leptin to suppress WAT lipogenesis in rats is lost when hypothalamic phosphoinositide 3-kinase signaling is prevented or when sympathetic denervation of adipose tissue is performed. MBH leptin suppresses the endocannabinoid anandamide in WAT, and, when this suppression of endocannabinoid tone is prevented by systemic CB1 receptor activation, MBH leptin fails to suppress WAT lipogenesis. These data suggest that the increased endocannabinoid tone observed in obesity is linked to a failure of central leptin signaling to restrain peripheral endocannabinoids.


Cell Metabolism | 2011

Brain insulin controls adipose tissue lipolysis and lipogenesis

Thomas Scherer; James O'Hare; Kelly A. Diggs-Andrews; Martina Schweiger; Bob Cheng; Claudia Lindtner; Elizabeth Zielinski; Prashant Vempati; Kai Su; Shveta Dighe; Thomas Milsom; Michelle A. Puchowicz; Ludger Scheja; Rudolf Zechner; Simon J. Fisher; Stephen F. Previs; Christoph Buettner

White adipose tissue (WAT) dysfunction plays a key role in the pathogenesis of type 2 diabetes (DM2). Unrestrained WAT lipolysis results in increased fatty acid release, leading to insulin resistance and lipotoxicity, while impaired de novo lipogenesis in WAT decreases the synthesis of insulin-sensitizing fatty acid species like palmitoleate. Here, we show that insulin infused into the mediobasal hypothalamus (MBH) of Sprague-Dawley rats increases WAT lipogenic protein expression, inactivates hormone-sensitive lipase (Hsl), and suppresses lipolysis. Conversely, mice that lack the neuronal insulin receptor exhibit unrestrained lipolysis and decreased de novo lipogenesis in WAT. Thus, brain and, in particular, hypothalamic insulin action play a pivotal role in WAT functionality.


Proceedings of the National Academy of Sciences of the United States of America | 2009

Oxytocin is an anabolic bone hormone

Roberto Tamma; Graziana Colaianni; Ling-Ling Zhu; Adriana DiBenedetto; Giovanni Greco; Gabriella Montemurro; Nicola Patano; Maurizio Strippoli; Rosaria Vergari; L. Mancini; Silvia Colucci; Maria Grano; Roberta Faccio; Xuan Liu; Jianhua Li; Sabah Usmani; Marilyn Bachar; Itai Bab; Katsuhiko Nishimori; Larry J. Young; Christoph Buettner; Jameel Iqbal; Li Sun; Mone Zaidi; Alberta Zallone

We report that oxytocin (OT), a primitive neurohypophyseal hormone, hitherto thought solely to modulate lactation and social bonding, is a direct regulator of bone mass. Deletion of OT or the OT receptor (Oxtr) in male or female mice causes osteoporosis resulting from reduced bone formation. Consistent with low bone formation, OT stimulates the differentiation of osteoblasts to a mineralizing phenotype by causing the up-regulation of BMP-2, which in turn controls Schnurri-2 and 3, Osterix, and ATF-4 expression. In contrast, OT has dual effects on the osteoclast. It stimulates osteoclast formation both directly, by activating NF-κB and MAP kinase signaling, and indirectly through the up-regulation of RANK-L. On the other hand, OT inhibits bone resorption by mature osteoclasts by triggering cytosolic Ca2+ release and NO synthesis. Together, the complementary genetic and pharmacologic approaches reveal OT as a novel anabolic regulator of bone mass, with potential implications for osteoporosis therapy.


Nature Communications | 2013

De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health

Leah Eissing; Thomas Scherer; Klaus Tödter; Uwe Knippschild; Jan Willem M. Greve; Wim A. Buurman; Hans O. Pinnschmidt; Sander S. Rensen; Anna Maria Wolf; Alexander Bartelt; Joerg Heeren; Christoph Buettner; Ludger Scheja

Clinical interest in de novo lipogenesis has been sparked by recent studies in rodents demonstrating that de novo lipogenesis specifically in white adipose tissue produces the insulin-sensitizing fatty acid palmitoleate. By contrast, hepatic lipogenesis is thought to contribute to metabolic disease. How de novo lipogenesis in white adipose tissue versus liver is altered in human obesity and insulin resistance is poorly understood. Here we show that lipogenic enzymes and the glucose transporter-4 are markedly decreased in white adipose tissue of insulin-resistant obese individuals compared with non-obese controls. By contrast, lipogenic enzymes are substantially upregulated in the liver of obese subjects. Bariatric weight loss restored de novo lipogenesis and glucose transporter-4 gene expression in white adipose tissue. Notably, lipogenic gene expression in both white adipose tissue and liver was strongly linked to the expression of carbohydrate-responsive element-binding protein-β and to metabolic risk markers. Thus, de novo lipogenesis predicts metabolic health in humans in a tissue-specific manner and is likely regulated by glucose-dependent carbohydrate-responsive element-binding protein activation.


Gastroenterology | 2012

Hepatic cannabinoid receptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice.

Jie Liu; Liang Zhou; Keming Xiong; Grzegorz Godlewski; Bani Mukhopadhyay; Joseph Tam; Shi Yin; Peter Gao; Xin Shan; James Pickel; Ramon Bataller; James O'Hare; Thomas Scherer; Christoph Buettner; George Kunos

BACKGROUND & AIMS Obesity-related insulin resistance contributes to cardiovascular disease. Cannabinoid receptor-1 (CB(1)) blockade improves insulin sensitivity in obese animals and people, suggesting endocannabinoid involvement. We explored the role of hepatic CB(1) in insulin resistance and inhibition of insulin signaling pathways. METHODS Wild-type mice and mice with disruption of CB(1) (CB(1)(-/-) mice) or with hepatocyte-specific deletion or transgenic overexpression of CB(1) were maintained on regular chow or a high-fat diet (HFD) to induce obesity and insulin resistance. Hyperinsulinemic-euglycemic clamp analysis was used to analyze the role of the liver and hepatic CB(1) in HFD-induced insulin resistance. The cellular mechanisms of insulin resistance were analyzed in mouse and human isolated hepatocytes using small interfering or short hairpin RNAs and lentiviral knockdown of gene expression. RESULTS The HFD induced hepatic insulin resistance in wild-type mice, but not in CB(1)(-/-) mice or mice with hepatocyte-specific deletion of CB(1). CB(1)(-/-) mice that overexpressed CB(1) specifically in hepatocytes became hyperinsulinemic as a result of reduced insulin clearance due to down-regulation of the insulin-degrading enzyme. However, they had increased hepatic glucose production due to increased glycogenolysis, indicating hepatic insulin resistance; this was further increased by the HFD. In mice with hepatocytes that express CB(1), the HFD or CB(1) activation induced the endoplasmic reticulum stress response via activation of the Bip-PERK-eIF2α protein translation pathway. In hepatocytes isolated from human or mouse liver, CB(1) activation caused endoplasmic reticulum stress-dependent suppression of insulin-induced phosphorylation of akt-2 via phosphorylation of IRS1 at serine-307 and by inducing the expression of the serine and threonine phosphatase Phlpp1. Expression of CB(1) was up-regulated in samples from patients with nonalcoholic fatty liver disease. CONCLUSIONS Endocannabinoids contribute to diet-induced insulin resistance in mice via hepatic CB(1)-mediated inhibition of insulin signaling and clearance.


PLOS ONE | 2009

Humanin: A Novel Central Regulator of Peripheral Insulin Action

Radhika Muzumdar; Derek M. Huffman; Gil Atzmon; Christoph Buettner; Laura J. Cobb; Sigal Fishman; Temuri Budagov; Lingguang Cui; Francine Einstein; Aruna D. Poduval; David Hwang; Nir Barzilai; Pinchas Cohen

Background Decline in insulin action is a metabolic feature of aging and is involved in the development of age-related diseases including Type 2 Diabetes Mellitus (T2DM) and Alzheimers disease (AD). A novel mitochondria-associated peptide, Humanin (HN), has a neuroprotective role against AD-related neurotoxicity. Considering the association between insulin resistance and AD, we investigated if HN influences insulin sensitivity. Methods and Findings Using state of the art clamp technology, we examined the role of central and peripheral HN on insulin action. Continuous infusion of HN intra-cerebro-ventricularly significantly improved overall insulin sensitivity. The central effects of HN on insulin action were associated with activation of hypothalamic STAT-3 signaling; effects that were negated by co-inhibition of hypothalamic STAT-3. Peripheral intravenous infusions of novel and potent HN derivatives reproduced the insulin-sensitizing effects of central HN. Inhibition of hypothalamic STAT-3 completely negated the effects of IV HN analog on liver, suggesting that the hepatic actions of HN are centrally mediated. This is consistent with the lack of a direct effect of HN on primary hepatocytes. Furthermore, single treatment with a highly-potent HN analog significantly lowered blood glucose in Zucker diabetic fatty rats. Based upon the link of HN with two age-related diseases, we examined if there were age associated changes in HN levels. Indeed, the amount of detectable HN in hypothalamus, skeletal muscle, and cortex was decreased with age in rodents, and circulating levels of HN were decreased with age in humans and mice. Conclusions We conclude that the decline in HN with age could play a role in the pathogenesis of age-related diseases including AD and T2DM. HN represents a novel link between T2DM and neurodegeneration and along with its analogues offers a potential therapeutic tool to improve insulin action and treat T2DM.


Molecular Cell | 2015

Mitochondrial Shape Governs BAX-Induced Membrane Permeabilization and Apoptosis

Thibaud T. Renault; Konstantinos V. Floros; Rana Elkholi; Kelly-Ann Corrigan; Yulia Kushnareva; Shira Y. Wieder; Claudia Lindtner; Madhavika N. Serasinghe; James J. Asciolla; Christoph Buettner; Donald D. Newmeyer; Jerry E. Chipuk

Proapoptotic BCL-2 proteins converge upon the outer mitochondrial membrane (OMM) to promote mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Here we investigated the mechanistic relationship between mitochondrial shape and MOMP and provide evidence that BAX requires a distinct mitochondrial size to induce MOMP. We utilized the terminal unfolded protein response pathway to systematically define proapoptotic BCL-2 protein composition after stress and then directly interrogated their requirement for a productive mitochondrial size. Complementary biochemical, cellular, in vivo, and ex vivo studies reveal that Mfn1, a GTPase involved in mitochondrial fusion, establishes a mitochondrial size that is permissive for proapoptotic BCL-2 family function. Cells with hyperfragmented mitochondria, along with size-restricted OMM model systems, fail to support BAX-dependent membrane association and permeabilization due to an inability to stabilize BAXα9·membrane interactions. This work identifies a mechanistic contribution of mitochondrial size in dictating BAX activation, MOMP, and apoptosis.


Endocrinology and Metabolism Clinics of North America | 2014

Mechanisms of Glucocorticoid-Induced Insulin Resistance: Focus on Adipose Tissue Function and Lipid Metabolism

Eliza B. Geer; Julie Islam; Christoph Buettner

Glucocorticoids (GCs) are critical in the regulation of the stress response, inflammation and energy homeostasis. Excessive GC exposure results in whole-body insulin resistance, obesity, cardiovascular disease, and ultimately decreased survival, despite their potent anti-inflammatory effects. This apparent paradox may be explained by the complex actions of GCs on adipose tissue functionality. The wide prevalence of oral GC therapy makes their adverse systemic effects an important yet incompletely understood clinical problem. This article reviews the mechanisms by which supraphysiologic GC exposure promotes insulin resistance, focusing in particular on the effects on adipose tissue function and lipid metabolism.


Journal of Clinical Investigation | 2005

Severe impairment in liver insulin signaling fails to alter hepatic insulin action in conscious mice

Christoph Buettner; Rima Patel; Evan D. Muse; Sanjay Bhanot; Brett P. Monia; Rob McKay; Silvana Obici; Luciano Rossetti

Insulin exerts its potent effects on hepatic glucose fluxes via direct and indirect mechanisms. Whereas a liver-specific insulin receptor (IR) knockout (LIRKO) mouse exhibits glucose intolerance as well as insulin resistance, it is unclear whether a more acute decrease in the expression of hepatic IR would be sufficient to induce hepatic insulin resistance. Here we report that the downregulation of hepatic IR expression by up to 95% does not modify hepatic insulin action. The i.p. administration (2 injections over 1 week) of an antisense oligodeoxynucleotide (ASO) directed to reduce insulin expression downregulated hepatic IR expression in C57BL6J mice. A high dose of IR-ASO decreased IR protein approximately 95%, while a control-ASO failed to modify IR expression. At this dose, the IR-ASO also decreased IR expression in adipose tissue but did not significantly decrease IR expression in hypothalamus or skeletal muscle. Insulin action was assessed with insulin clamp studies in conscious mice. The rate of glucose infusion during the clamp studies was comparable in control-ASO- and IR-ASO-treated mice. Importantly, the depletion of liver IR protein markedly impaired downstream insulin signaling in the liver, but it failed to modify the rate of glucose production. Thus, near ablation of liver IR does not alter insulin action on glucose production.

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Thomas Scherer

Medical University of Vienna

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Claudia Lindtner

Icahn School of Medicine at Mount Sinai

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Andrew C. Shin

Icahn School of Medicine at Mount Sinai

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Elizabeth Zielinski

Icahn School of Medicine at Mount Sinai

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Douglas J. Oberlin

Icahn School of Medicine at Mount Sinai

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Henry H. Ruiz

Icahn School of Medicine at Mount Sinai

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Jameel Iqbal

Icahn School of Medicine at Mount Sinai

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James O'Hare

Icahn School of Medicine at Mount Sinai

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Jianhua Li

Icahn School of Medicine at Mount Sinai

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