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Dive into the research topics where Kirk M. Habegger is active.

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Featured researches published by Kirk M. Habegger.


Physiological Reviews | 2012

Sirtuin 1 and Sirtuin 3: Physiological Modulators of Metabolism

Ruben Nogueiras; Kirk M. Habegger; Nilika Chaudhary; Brian Finan; Alexander S. Banks; Marcelo O. Dietrich; Tamas L. Horvath; David A. Sinclair; Paul T. Pfluger; Matthias H. Tschöp

The sirtuins are a family of highly conserved NAD(+)-dependent deacetylases that act as cellular sensors to detect energy availability and modulate metabolic processes. Two sirtuins that are central to the control of metabolic processes are mammalian sirtuin 1 (SIRT1) and sirtuin 3 (SIRT3), which are localized to the nucleus and mitochondria, respectively. Both are activated by high NAD(+) levels, a condition caused by low cellular energy status. By deacetylating a variety of proteins that induce catabolic processes while inhibiting anabolic processes, SIRT1 and SIRT3 coordinately increase cellular energy stores and ultimately maintain cellular energy homeostasis. Defects in the pathways controlled by SIRT1 and SIRT3 are known to result in various metabolic disorders. Consequently, activation of sirtuins by genetic or pharmacological means can elicit multiple metabolic benefits that protect mice from diet-induced obesity, type 2 diabetes, and nonalcoholic fatty liver disease.


Science Translational Medicine | 2013

Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents, Monkeys, and Humans

Brian Finan; Tao Ma; Nickki Ottaway; Timo D. Müller; Kirk M. Habegger; Kristy M. Heppner; Henriette Kirchner; Jenna Holland; Jazzminn Hembree; Christine Raver; Sarah Kathleen Haas Lockie; David L. Smiley; Vasily Gelfanov; Bin Yang; Susanna M. Hofmann; Dennis Bruemmer; Daniel J. Drucker; Paul T. Pfluger; Diego Perez-Tilve; Jaswant Gidda; Louis Vignati; Lianshan Zhang; Jonathan Hauptman; Michele Lau; Mathieu Brecheisen; Sabine Uhles; William Riboulet; Emmanuelle Hainaut; Elena Sebokova; Karin Conde-Knape

Compared to best-in-class GLP-1 mono-agonists, unimolecular co-agonists of GLP-1 and GIP with optimized pharmacokinetics enhance glycemic and metabolic benefits in mammals. “Twincretins”: Two Is Better than One Despite obesity-linked diabetes approaching worldwide epidemic proportions and the growing recognition of it as a global health challenge, safe and effective medicines have remained largely elusive. Pharmacological options targeting multiple obesity and diabetes signaling pathways offer greater therapeutic potential compared to molecules targeting a single pathway. Finan et al. now report the discovery, characterization, and translational efficacy of a single molecule that acts equally on the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). In rodent models of obesity and diabetes, this dual incretin co-agonist more effectively lowered body fat and corrected hyperglycemia than selective mono-agonists for the GLP-1 and GIP receptors. An enhanced insulinotropic effect translated from rodents to monkeys and humans, with substantially improved levels of glycosylated hemoglobin A1c (HbA1c) in humans with type 2 diabetes. The dual incretin was engineered with selective chemical modifications to enhance pharmacokinetics. This, in combination with its inherent mixed agonism, lowered the drug dose and ameliorated the dose-limiting nausea that has plagued selective GLP-1 therapies. These dual incretin co-agonists signify a new direction for unimolecular combination therapy and represent a new class of drug candidates for the treatment of metabolic diseases. We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). Furthermore, this co-agonist exhibited synergism in reducing fat mass in obese rodents, whereas a selective GIP agonist demonstrated negligible weight-lowering efficacy. The unimolecular dual incretins corrected two causal mechanisms of diabesity, adiposity-induced insulin resistance and pancreatic insulin deficiency, more effectively than did selective mono-agonists. The duration of action of the unimolecular dual incretins was refined through site-specific lipidation or PEGylation to support less frequent administration. These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1–mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1–based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.


Nature Medicine | 2015

A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents

Brian Finan; Bin Yang; Nickki Ottaway; David L. Smiley; Tao Ma; Christoffer Clemmensen; Joe Chabenne; Lianshan Zhang; Kirk M. Habegger; Katrin Fischer; Jonathan E. Campbell; Darleen A. Sandoval; Randy J. Seeley; Konrad Bleicher; Sabine Uhles; William Riboulet; Jürgen Funk; Cornelia Hertel; Sara Belli; Elena Sebokova; Karin Conde-Knape; Anish Konkar; Daniel J. Drucker; Vasily Gelfanov; Paul T. Pfluger; Timo D. Müller; Diego Perez-Tilve; Richard D. DiMarchi; Matthias H. Tschöp

We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity. These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders.


Nature Medicine | 2012

Targeted estrogen delivery reverses the metabolic syndrome

Brian Finan; Bin Yang; Nickki Ottaway; Kerstin Stemmer; Timo D. Müller; Chun Xia Yi; Kirk M. Habegger; Sonja C. Schriever; Cristina García-Cáceres; Dhiraj G. Kabra; Jazzminn Hembree; Jenna Holland; Christine Raver; Randy J. Seeley; Wolfgang Hans; Martin Irmler; Johannes Beckers; Martin Hrabě de Angelis; Joseph P. Tiano; Franck Mauvais-Jarvis; Diego Perez-Tilve; Paul T. Pfluger; Lianshan Zhang; Vasily Gelfanov; Richard D. DiMarchi; Matthias H. Tschöp

We report the development of a new combinatorial approach that allows for peptide-mediated selective tissue targeting of nuclear hormone pharmacology while eliminating adverse effects in other tissues. Specifically, we report the development of a glucagon-like peptide-1 (GLP-1)-estrogen conjugate that has superior sex-independent efficacy over either of the individual hormones alone to correct obesity, hyperglycemia and dyslipidemia in mice. The therapeutic benefits are driven by pleiotropic dual hormone action to improve energy, glucose and lipid metabolism, as shown by loss-of-function models and genetic action profiling. Notably, the peptide-based targeting strategy also prevents hallmark side effects of estrogen in male and female mice, such as reproductive endocrine toxicity and oncogenicity. Collectively, selective activation of estrogen receptors in GLP-1–targeted tissues produces unprecedented efficacy to enhance the metabolic benefits of GLP-1 agonism. This example of targeting the metabolic syndrome represents the discovery of a new class of therapeutics that enables synergistic co-agonism through peptide-based selective delivery of small molecules. Although our observations with the GLP-1–estrogen conjugate justify translational studies for diabetes and obesity, the multitude of other possible combinations of peptides and small molecules may offer equal promise for other diseases.


Nature Reviews Endocrinology | 2010

The metabolic actions of glucagon revisited

Kirk M. Habegger; Kristy M. Heppner; Nori Geary; Timothy J. Bartness; Richard D. DiMarchi; Matthias H. Tschöp

The initial identification of glucagon as a counter-regulatory hormone to insulin revealed this hormone to be of largely singular physiological and pharmacological purpose. Glucagon agonism, however, has also been shown to exert effects on lipid metabolism, energy balance, body adipose tissue mass and food intake. The ability of glucagon to stimulate energy expenditure, along with its hypolipidemic and satiating effects, in particular, make this hormone an attractive pharmaceutical agent for the treatment of dyslipidemia and obesity. Studies that describe novel preclinical applications of glucagon, alone and in concert with glucagon-like peptide 1 agonism, have revealed potential benefits of glucagon agonism in the treatment of the metabolic syndrome. Collectively, these observations challenge us to thoroughly investigate the physiology and therapeutic potential of insulins long-known opponent.


Diabetes | 2013

Fibroblast Growth Factor 21 Mediates Specific Glucagon Actions

Kirk M. Habegger; Kerstin Stemmer; Christine C. Cheng; Timo D. Müller; Kristy M. Heppner; Nickki Ottaway; Jenna Holland; Jazzminn Hembree; David L. Smiley; Vasily Gelfanov; Radha Krishna; Ayman M. Arafat; Anish Konkar; Sara Belli; Martin Kapps; Stephen C. Woods; Susanna M. Hofmann; David A. D’Alessio; Paul T. Pfluger; Diego Perez-Tilve; Randy J. Seeley; Morichika Konishi; Nobuyujki Itoh; Alexei Kharitonenkov; Joachim Spranger; Richard D. DiMarchi; Matthias H. Tschöp

Glucagon, an essential regulator of glucose homeostasis, also modulates lipid metabolism and promotes weight loss, as reflected by the wasting observed in glucagonoma patients. Recently, coagonist peptides that include glucagon agonism have emerged as promising therapeutic candidates for the treatment of obesity and diabetes. We developed a novel stable and soluble glucagon receptor (GcgR) agonist, which allowed for in vivo dissection of glucagon action. As expected, chronic GcgR agonism in mice resulted in hyperglycemia and lower body fat and plasma cholesterol. Notably, GcgR activation also raised hepatic expression and circulating levels of fibroblast growth factor 21 (FGF21). This effect was retained in isolated primary hepatocytes from wild-type (WT) mice, but not GcgR knockout mice. We confirmed this link in healthy human volunteers, where injection of natural glucagon increased plasma FGF21 within hours. Functional relevance was evidenced in mice with genetic deletion of FGF21, where GcgR activation failed to induce the body weight loss and lipid metabolism changes observed in WT mice. Taken together, these data reveal for the first time that glucagon controls glucose, energy, and lipid metabolism at least in part via FGF21-dependent pathways.


Journal of Peptide Science | 2012

Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21.

Timo D. Müller; Lorraine Sullivan; Kirk M. Habegger; Chun-Xia Yi; Dhiraj G. Kabra; Erin Grant; Nickki Ottaway; Radha Krishna; Jenna Holland; Jazzminn Hembree; Diego Perez-Tilve; Paul T. Pfluger; Michael J. DeGuzman; Marc E. Siladi; Douglas W. Axelrod; Richard D. DiMarchi; Jason Pinkstaff; Matthias H. Tschöp

The identification of leptin as a mediator of body weight regulation provided much initial excitement for the treatment of obesity. Unfortunately, leptin monotherapy is insufficient in reversing obesity in rodents or humans. Recent findings suggest that amylin is able to restore leptin sensitivity and when used in combination with leptin enhances body weight loss in obese rodents and humans. However, as the uniqueness of this combination therapy remains unclear, we assessed whether co‐administration of leptin with other weight loss‐inducing hormones equally restores leptin responsiveness in diet‐induced obese (DIO) mice. Accordingly, we report here the design and characterization of a series of site‐specifically enhanced leptin analogs of high potency and sustained action that, when administered in combination with exendin‐4 or fibroblast growth factor 21 (FGF21), restores leptin responsiveness in DIO mice after an initial body weight loss of 30%. Using either combination, body weight loss was enhanced compared with either exendin‐4 or FGF21 monotherapy, and leptin alone was sufficient to maintain the reduced body weight. In contrast, leptin monotherapy proved ineffective when identical weight loss was induced by caloric restriction alone over a comparable time. Accordingly, we find that a hypothalamic counter‐regulatory response to weight loss, assessed using changes in hypothalamic agouti related peptide (AgRP) levels, is triggered by caloric restriction, but blunted by treatment with exendin‐4. We conclude that leptin re‐sensitization requires pharmacotherapy but does not appear to be restricted to a unique signaling pathway. Our findings provide preclinical evidence that high activity, long‐acting leptin analogs are additively efficacious when used in combination with other weight‐lowering agents. Copyright


Physiology & Behavior | 2010

Glucagon regulation of energy metabolism.

Kristy M. Heppner; Kirk M. Habegger; Jonathan Day; Paul T. Pfluger; Diego Perez-Tilve; Brian P. Ward; Vasily Gelfanov; Steve Woods; Richard D. DiMarchi; Matthias H. Tschöp

Glucagon has long been known as a counter-regulatory hormone to insulin of fundamental importance to glucose homeostasis. Its prominent ability to stimulate glycogenolysis and gluconeogenesis, has historically cast this peptide as one hormone where the metabolic consequences of increasing blood glucose levels, especially in obesity, are viewed largely as being deleterious. This perspective may be changing in light of emerging data and reconsideration of historic studies, which suggest that glucagon has beneficial effects on body fat mass, food intake, and energy expenditure. In this review, we discuss the mechanisms of glucagon-mediated body weight regulation as well as possible novel therapeutic approaches in the treatment of obesity and glucose intolerance that may arise from these findings. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.


The Journal of Neuroscience | 2010

CNS Leptin Action Modulates Immune Response and Survival in Sepsis

Johannes Tschöp; Ruben Nogueiras; Sarah Haas-Lockie; Kevin R. Kasten; Tamara R. Castañeda; Nadine Huber; Kelsey Guanciale; Diego Perez-Tilve; Kirk M. Habegger; Nickki Ottaway; Stephen C. Woods; Brian J. Oldfield; Iain J. Clarke; Streamson C. Chua; Farooqi Is; Stephen O'Rahilly; Charles C. Caldwell; M. Tschöp

Sepsis describes a complex clinical syndrome that results from an infection, setting off a cascade of systemic inflammatory responses that can lead to multiple organ failure and death. Leptin is a 16 kDa adipokine that, among its multiple known effects, is involved in regulating immune function. Here we demonstrate that leptin deficiency in ob/ob mice leads to higher mortality and more severe organ damage in a standard model of sepsis in mice [cecal ligation and puncture (CLP)]. Moreover, systemic leptin replacement improved the immune response to CLP. Based on the molecular mechanisms of leptin regulation of energy metabolism and reproductive function, we hypothesized that leptin acts in the CNS to efficiently coordinate peripheral immune defense in sepsis. We now report that leptin signaling in the brain increases survival during sepsis in leptin-deficient as well as in wild-type mice and that endogenous CNS leptin action is required for an adequate systemic immune response. These findings reveal the existence of a relevant neuroendocrine control of systemic immune defense and suggest a possible therapeutic potential for leptin analogs in infectious disease.


Cell | 2016

Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease.

Brian Finan; Christoffer Clemmensen; Zhimeng Zhu; Kerstin Stemmer; Karine Gauthier; Luisa Müller; Meri De Angelis; Kristin Moreth; Frauke Neff; Diego Perez-Tilve; Katrin Fischer; Dominik Lutter; Miguel A. Sánchez-Garrido; Peng Liu; Jan Tuckermann; Mohsen Malehmir; Marc E. Healy; Achim Weber; Mathias Heikenwalder; Martin Jastroch; Maximilian Kleinert; Sigrid Jall; Sara J. Brandt; Frédéric Flamant; Karl-Werner Schramm; Heike Biebermann; Yvonne Döring; Christian Weber; Kirk M. Habegger; Michaela Keuper

Glucagon and thyroid hormone (T3) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T3 actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T3 action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.

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Nickki Ottaway

University of Cincinnati

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Richard D. DiMarchi

Indiana University Bloomington

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Jenna Holland

University of Cincinnati

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David L. Smiley

Indiana University Bloomington

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