SummaryDespite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.

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PRKAG2 mutations are responsible for a diverse phenotype and not only the familial form of the WPW syndrome. Familial occurrence of right bundle branch block, sinus bradycardia, and short PR interval should raise suspicion of a mutant PRKAG2 gene.

AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as αβγ complexes, whose regulatory γ subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the γ2 subunit exhibit a phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that γ2 AMPK activation downregulates fundamental sinoatrial cell pacemaker mechanisms to lower heart rate, including sarcolemmal hyperpolarization-activated current (I f) and ryanodine receptor-derived diastolic local subsarcolemmal Ca2+ release. In contrast, loss of γ2 AMPK induces a reciprocal phenotype of increased heart rate, and prevents the adaptive intrinsic bradycardia of endurance training. Our results reveal that in mammals, for which heart rate is a key determinant of cardiac energy demand, AMPK functions in an organ-specific manner to maintain cardiac energy homeostasis and determines cardiac physiological adaptation to exercise by modulating intrinsic sinoatrial cell behavior.

Aims The anatomic substrates for atrioventricular nodal re-entry remain enigmatic, but require knowledge of the normal arrangement of the inputs and exist from the atrioventricular node. This knowledge is crucial to understand the phenomenon of atrioventricular nodal re-entry. Methods and results We studied 20 human hearts with serial sections covering the entirety of the triangle of Koch and the cavotricuspid isthmus. We determined the location of the atrioventricular conduction axis and the connections between the specialized cardiomyocytes of the conduction axis and the adjacent working atrial myocardium. The atrioventricular node was found at the apex of the triangle of Koch, with entry of the conduction axis to the central fibrous body providing the criterion for distinction of the bundle of His. We found marked variation in the inferior extensions of the node, the shape of the node, the presence or absence of a connecting bridge within the myocardium of the cavotricuspid isthmus, the connections between the compact node and the myocardium of the atrial septum, the presence of transitional cardiomyocytes, and the ‘last’ connection between the working atrial myocardium and the conduction axis before it became the bundle of His. Conclusion The observed variations of the inferior extensions, combined with the arrangement of the ‘last’ connections between the atrial myocardium and the conduction axis prior to its insulation as the bundle of His, provide compelling evidence to support the concept for atrioventricular nodal re-entry as advanced by Katritsis and Becker.

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