Antiobesity Strategy Targets Energy Economy Safeguards
Authors: Michel Vivaudou, André Terzic
Journal: Molecular Therapy (2015)

A fundamental barrier in obesity management is that caloric restriction triggers energy-conserving responses that evolved to prevent body weight loss. ATP-sensitive potassium (KATP) channels have been identified as safeguards controlling energy expenditure in skeletal muscles and thereby key factors determining body weight.1Alekseev AE Reyes S Yamada S Hodgson-Zingman DM Sattiraju S Zhu Z et al.Sarcolemmal ATP-sensitive K+ channels control energy expenditure determining body weight.Cell Metab. 2010; 11: 58-69Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar In this issue of Molecular Therapy, Koganti and colleagues report the successful reduction of muscle energy efficiency through targeted intramuscular injections of cell-penetrating vivo-morpholinos to prevent translation of the channel pore-forming Kir6.2 subunit.2Koganti SRK Zhu Z Subbotina E Gao Z Sierra A Proenza M et al.Disruption of KATP channel expression in skeletal muscle by targeted oligonucleotide delivery promotes activity-linked thermogenesis.Mol Ther. 2015; 23: 707-716Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar In this elegant proof-of-concept study, the authors demonstrate localized reduction of KATP channel expression and function, leading in turn to an increase in activity-related energy consumption, without compromising exercise tolerance. This report opens a new avenue of investigation in targeted therapies aiming to control weight management. Obesity reflects an imbalance between calorie intake and expenditure. At present, more than 1 billion adults worldwide are considered overweight, underscoring a rampant epidemic.3Valentino MA Terzic A Waldman SA Sizing up pharmacotherapy for obesity.Clin Transl Sci. 2010; 3: 123-125Crossref PubMed Scopus (4) Google Scholar The global prevalence of obesity has precipitated a major escalation in comorbidities associated with an increase in overall mortality.4Terzic A Waldman S Chronic diseases: the emerging pandemic.Clin Transl Sci. 2011; 4: 225-226Crossref PubMed Scopus (102) Google Scholar Beyond intensive counseling and change in lifestyle, diverse strategies targeting weight loss are being pursued.5Rueda-Clausen CF Padwal RS Sharma AM New pharmacological approaches for obesity management.Nat Rev Endocrinol. 2013; 9: 467-478Crossref PubMed Scopus (35) Google Scholar Progress is reflected by US Food and Drug Administration approval of new medications for chronic weight management in obese patients, such as lorcaserin and phentermine/topiramate. Yet antiobesity drug therapy has been largely unsuccessful because of lack of efficacy, poor adherence, and adverse effects.6Kim GW Lin JE Blomain ES Waldman SA Antiobesity pharmacotherapy: new drugs and emerging targets.Clin Pharmacol Ther. 2014; 95: 53-66Crossref PubMed Scopus (143) Google Scholar Elucidating the molecular pathways that underlie the caloric intake–expenditure equilibrium is necessary to inform the selection of promising therapeutic targets. Indeed, a deeper insight into the innate mechanisms regulating appetite, nutrient exposure, and energy balance is warranted to aid in the discovery and future development of next-generation therapies. Stimulation of energy expenditure may be a potent strategy for obesity treatment. KATP channels, expressed at high density in striated muscles and other excitable tissues, are established membrane sensors of ATP/ADP.7Flagg TP Enkvetchakul D Koster JC Nichols CG Muscle KATP channels: recent insights to energy sensing and myoprotection.Physiol Rev. 2010; 90: 799-829Crossref PubMed Scopus (218) Google Scholar,8Olson TM Terzic A Human KATP channelopathies: diseases of metabolic homeostasis.Pflugers Arch. 2010; 460: 295-306Crossref PubMed Scopus (96) Google Scholar,9Terzic A Alekseev AE Yamada S Reyes S Olson TM Advances in cardiac ATP-sensitive K+ channelopathies from molecules to populations.Circ Arrhythm Electrophysiol. 2011; 4: 577-585Crossref PubMed Scopus (12) Google Scholar It has been postulated that under conditions of energy deficit, activation of channel complexes would result in protective energy economy, whereas under energy surplus, downregulation of KATP channels would increase thermogenesis.10Reyes S Park S Terzic A Alekseev AE KATP channels process nucleotide signals in muscle thermogenic response.Crit Rev Biochem Mol Biol. 2010; 45: 506-519Crossref PubMed Scopus (13) Google Scholar As such, KATP channels provide a low-fuel warning that signals muscle fibers to slow down and avoid irreversible energy depletion. Through tight regulation by adenine nucleotides and integration with metabolic pathways, muscle KATP channels seem to sense both static metabolic levels and the dynamics of energy consumption, thus maintaining an optimal balance between lost heat production and useful mechanical work.11Alekseev AE Hodgson DM Karger AB Park S Zingman LV Terzic A ATP-sensitive K+ channel channel/enzyme multimer: metabolic gating in the heart.J Mol Cell Cardiol. 2005; 38: 895-905Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Without functional KATP channels, energy efficiency decreases and muscles burn more calories than normal.1Alekseev AE Reyes S Yamada S Hodgson-Zingman DM Sattiraju S Zhu Z et al.Sarcolemmal ATP-sensitive K+ channels control energy expenditure determining body weight.Cell Metab. 2010; 11: 58-69Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Thus, weight loss could be achieved without additional exercise, by “simply” reducing the activity of skeletal muscle KATP channels. A pharmacological approach is conceivable, as numerous molecules are known to modulate KATP channels by binding to their regulatory SUR subunit.12Jahangir A Terzic A KATP channel therapeutics at the bedside.J Mol Cell Cardiol. 2005; 39: 99-112Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Unfortunately, blockers of KATP channels specific for skeletal muscle do not yet exist and are unlikely to be discovered soon, given that comparable channels (incorporating isoform SUR2) are also found in cardiac and smooth muscle.13Moreau C Prost AL Dérand R Vivaudou M SUR, ABC proteins targeted by KATP channel openers.J Mol Cell Cardiol. 2005; 38: 951-963Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar In the new work, Koganti and colleagues2Koganti SRK Zhu Z Subbotina E Gao Z Sierra A Proenza M et al.Disruption of KATP channel expression in skeletal muscle by targeted oligonucleotide delivery promotes activity-linked thermogenesis.Mol Ther. 2015; 23: 707-716Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar used an alternative approach of reducing protein levels by leveraging antisense oligonucleotides packaged as a morpholino for stability and coupled to a guanidine dendrimer for intracellular delivery (“vivo-morpholinos”).14Morcos PA Li Y Jiang S Vivo-Morpholinos: a non-peptide transporter delivers Morpholinos into a wide array of mouse tissues.Biotechniques. 2008; 45: 613-623Crossref PubMed Scopus (145) Google Scholar Using mice, the authors demonstrate that it is feasible to selectively knock down KATP channels in designated skeletal muscles by intramuscular injections of vivo-morpholinos targeting the Kir6.2 pore subunit of the channels.2Koganti SRK Zhu Z Subbotina E Gao Z Sierra A Proenza M et al.Disruption of KATP channel expression in skeletal muscle by targeted oligonucleotide delivery promotes activity-linked thermogenesis.Mol Ther. 2015; 23: 707-716Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar At the molecular level, application of vivo-morpholinos decreased Kir6.2 protein levels threefold (measured with western blot) and decreased channel functional expression to the same extent (measured by the patch-clamp technique). Importantly, these effects persisted for at least a week, and nearby muscles were not affected. These measurements demonstrate the efficacy of vivo-morpholinos in achieving a significant and long-lasting reduction of targeted KATP channel activity.2Koganti SRK Zhu Z Subbotina E Gao Z Sierra A Proenza M et al.Disruption of KATP channel expression in skeletal muscle by targeted oligonucleotide delivery promotes activity-linked thermogenesis.Mol Ther. 2015; 23: 707-716Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar The response of the fibers to exercise was assessed by monitoring membrane potential, action potential characteristics, and force. At rest, where it is thought that KATP channels are mostly inactive, there was little difference between treated and untreated fibers. Under prolonged stimulation, skeletal muscle adaptation is seen by a steady decline in action potential amplitude and force. Experiments on whole animals showed that exercising treated subjects produced more heat and consumed more oxygen than did the same treatment of controls. Based on these results, the authors suggest that anti-Kir6.2 vivo-morpholinos could be used to treat obesity, as they document that it is possible to reduce the expression of KATP channels in a specific muscle, thus directing that muscle to burn more calories than usual without disabling the muscle's mechanical function.2Koganti SRK Zhu Z Subbotina E Gao Z Sierra A Proenza M et al.Disruption of KATP channel expression in skeletal muscle by targeted oligonucleotide delivery promotes activity-linked thermogenesis.Mol Ther. 2015; 23: 707-716Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Selective knockdown in designated muscle areas seems particularly important, in that previous studies using Kir6.2-knockout models have implicated Kir6.2-dependent KATP channel activity required for attainment of the physiological benefits of exercise without injury.15Kane GC Behfar A Yamada S Perez-Terzic C O’Cochlain F Reyes S et al.ATP-sensitive K+ channel knockout compromises the metabolic benefit of exercise training, resulting in cardiac deficits.Diabetes. 2004; 53: S169-S175Crossref PubMed Scopus (91) Google Scholar The study by Koganti et al. thus provides an original approach to target KATP channel-dependent energy economy, introducing a fit-for-purpose experimental tool and opening a spectrum of new considerations. Which and how many muscles should be targeted to achieve significant weight loss? How predictable, how persistent, and how stable are the effects of vivo-morpholinos on channel density and ultimate outcome? Is there a concomitant loss of myoprotection conferred by KATP channels that would thereby limit treatment to nonexercising subjects? To what extent are genetic manipulation underpinning therapy and the invasive mode of intramuscular delivery, though feasible, safe and effective in the long term? Thus, the translational value of this promising approach, as a means to manage obesity, is predicated on further testing with demonstration of spatial and temporal effectiveness, and of a safe therapeutic index.