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Therapeutic Targeting of the cAMP and cGMP Pathway to Increase Brown Adipose Tissue Activity in Humans

English title Therapeutic Targeting of the cAMP and cGMP Pathway to Increase Brown Adipose Tissue Activity in Humans
Applicant Betz Matthias
Number 201065
Funding scheme Project funding (Div. I-III)
Research institution Abteilung Endokrinologie, Diabetologie und Metabolismus Universitätsspital Basel
Institution of higher education University of Basel - BS
Main discipline Endocrinology
Start/End 01.11.2021 - 31.10.2025
Approved amount 632'000.00
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All Disciplines (4)

Discipline
Endocrinology
Pharmacology, Pharmacy
Physiology : other topics
Pathophysiology

Keywords (8)

thermogenesis; brown adipose tissue; obesity; energy expenditure; cGMP; cAMP; inosine; isosorbitdinitrate

Lay Summary (German)

Lead
Das sogenannte braune Fettgewebe (BAT) wandelt chemische Energie, die in Fetten und Kohlenhydraten gespeichert ist, direkt in Wärme um und steigert den Energieverbrauch. Das vorliegende Projekt soll untersuchen, ob menschliches BAT durch die Substanzen Inosin respektive Isosorbid-dinitrat aktiviert werden kann.
Lay summary

BAT bei Erwachsenen ist mit einem geringeren Körpergewicht sowie günstigen Auswirkungen auf den Zucker- und Fettstoffwechsel verbunden. Es kann durch wiederholte intermittierende leichte Kälteeinwirkung aktiviert und sein Umfang vergrössert werden. Alternativ könnte ein Arzneimittel die Stoffwechselaktivität von BAT und den Energieverbrauch erhöhen. BAT wird physiologischerweise durch lokale Abgabe des Botenstoffs Noradrenalin aktiviert. Der therapeutische Einsatz von Noradrenalin und verwandter Substanzen ist jedoch aufgrund von  Nebenwirkungen wie erhöhter Herzfrequenz und Blutdruck eingeschränkt.

Noradrenalin erhöht in BAT u.a. Signalmoleküle cAMP und cGMP, die dann die weiteren molekularen Schritte der Wärmeproduktion aktivieren. Präklinische Versuche haben gezeigt, dass das natürlich vorkommende Nukleosid Adenosin BAT ebenfalls aktivieren kann, indem es die intrazellulären cAMP-Spiegel steigert. Allerdings wird Adenosin im Körper innerhalb von Sekunden abgebaut. Wir wollen untersuchen ob der natürlich vorkommende Adenosin-Metabolit Inosin humanes BAT ebenfalls stimulieren kann. Die intrazellulären cGMP-Spiegel werden durch sogenannte Nitropräparate erhöht, die seit Jahrzehnten zur Behandlung der koronaren Herzkrankheit eingesetzt werden.

Wir werden Inosin und das Nitropräparat Isosorbid-dinitrat im Vergleich zu Placebo  42 gesunden normalgewichtigen, gesunden Probanden sowie  10 adipösen Patienten geben und die Wirkung auf den Energieverbrauch des Körpers und die Aktivität des BAT messen.

Das vorgeschlagene Forschungsprogramm wird uns wichtige Einblicke in die Regulation von BAT und Thermogenese zu gewinnen. Aus klinischer Sicht könnte die hier vorgeschlagene Forschung dazu beitragen, vorhandene und erschwingliche Substanzen zu verwenden, um den Energieverbrauch therapeutisch zu erhöhen.

Direct link to Lay Summary Last update: 22.08.2021

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Associated projects

Number Title Start Funding scheme
167823 Influence of glucocorticoids on human brown adipose tissue and cold induced thermogenesis 01.05.2017 Ambizione

Abstract

Background: Weight loss regimens lead to a reduction in resting energy expenditure which counteracts weight loss and facilitates weight regain. Brown adipose tissue (BAT) has been demonstrated to be active in human adults and to be associated with lower body weight. BAT transfers chemical energy stored in lipids and carbohydrates directly into heat by short-circuiting the mitochondrial respiratory chain with uncoupling protein 1 (UCP1). It can be stimulated and expanded by repetitive intermittent mild cold exposure. Alternatively, pharmacological targeting of BAT activity could increase energy expenditure and thus reduce obesity. The classical transmitter activating BAT is the catecholamine norepinephrine. The therapeutic use of catecholamines is however limited due to systemic side effects such as increased heart rate and blood pressure. Within brown adipocytes the cAMP and cGMP second messenger pathways lead to increased lipolysis and activation of thermogenesis. The nucleoside adenosine has been shown to activate BAT both synergistically with and independently from norepinephrine by increasing intracellular levels of cAMP via agonism at A2A receptors (A2AR). However, the half-life of adenosine is very short. We propose therefore to use the adenosine metabolite inosine which is also an agonist at the A2AR and has a half-life of 15 h. Intracellular levels of cGMP are increased by stimulation of soluble guanylate cyclase (sGC) which is a target of nitric oxide. We propose to use isosorbide dinitrate which releases nitric oxide to increase intracellular cGMP levels and BAT activity.Aim: The aim of this study is to evaluate the efficacy of inosine and isosorbide dinitrate to activate and expand human BAT as compared to placebo.Hypothesis: We hypothesize that inosine and isosorbide dinitrate increase BAT activity.Design: The study will be performed as a randomized cross-over trial with three treatment phases separated by washout periods of at least four weeks. Allocation to treatment sequences will be randomized and both participants and investigators will be blinded. The primary outcome will be BAT activity as determined by FDG-PET/CT scanning after a controlled mild cold stimulus. Study population: 42 healthy, normal weight men; extension cohort of 10 healthy but obese men.Sample size considerations: In order to be able to detect a clinically significant difference in BAT activity of 25% and accounting for two active treatment phases compared to placebo we will need a minimum of 36 participants for a statistical power of 0.8 and an overall a-error of 0.05.Setting: The study will be performed at the Department of Endocrinology Diabetes and Metabolism and the Department of Clinical Research at the University Hospital Basel.Significance: The significance of the proposed research program is twofold: From the scientific point of view it will allow us to gain important insight into human BAT regulation and thermogenesis. From the clinical point of view, the efficacious treatment of obesity is still an unmet medical need. Bariatric surgery, which is currently the most effective treatment, is restricted in its usefulness due to cost and limited availability when compared to the large number of affected persons. The research proposed here will potentially allow to repurpose existing and affordable substances to increase energy expenditure thereby providing an additional therapeutic option to treat obesity.
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