Targeting-Adipose-Tissue-Lipid-Metabolism-to-Improve-Glucose-Metabolism-in-Cardiometabolic-Disease

Recently, we have shown that dietary polyphenols,including resveratrol and epigallocatechin-3-gallate, found naturally in red wine and greentea, have CR-like effects in overweight humans. 105,106Interestingly, our microarray data showed thatresveratrol supplementation affected the expressionof the master of lipophagy TFEB and improvedadipose tissue function in humans. 105,107 However,it needs to be determined whether lipophagymediatedlipid catabolism in adipose tissue isdirectly involved in the potential beneficialmetabolic effects of polyphenols. Finally, it hasbeen shown that autophagy might regulate lipidaccumulation by controlling the balance betweenwhite and brown adipose tissue mass, whichfavours lipid oxidation and increases systemicinsulin sensitivity by limiting FFA efflux. 27,29,108Overall, we propose that the success of modulatinglipophagy, as a potential strategy in themanagement of obesity, is largely dependent onthe fine tuning of all three steps in this pathway,namely autophagosome formation, lysososmalbreakdown, and final mitochondrial oxidation ofthe lipid cargo (Figure 2).CONCLUSION AND PERSPECTIVEResearch over the last decade has substantiallyincreased our understanding, but also addedcomplexity to the regulation of adipose tissuelipid metabolism in cMet diseases. Increased basaland desensitisation of catecholamine and NPstimulatedadipose tissue lipolysis, due todownregulation of the expression of the keylipolytic enzymes, is a hallmark of human obesity(Figure 2). However, there is no straightforwardrelationship between fat mass, systemic FFA flux,and the development of insulin resistance andcMet diseases. Nevertheless, the interest in antilipolyticdrugs, which have been used for decadesas a lipid-lowering agent, recently regained interestby the development of selective HSL and ATGLinhibitors. Partial inhibition of HSL shows promisingeffects, preventing extra weight gain by reshapingFFA fluxes and improving systemic glucosemetabolism via stimulation of adipose tissue DNL. 84However, long-term human clinical trials usingselective ATGL and HSL inhibitors are lacking.In contrast to this anti-lipolytic approach, the effectof increasing NP and catecholamine sensitivity/signalling, using NEP or PDE inhibitors, on lipidmetabolism needs to be investigated in more detail.Importantly, exaggerated inhibition or activationof ATL may result in excessive weight gain or thedevelopment of cachexia when tissue FFA uptake,esterification, and oxidation are not adaptedaccordingly. In addition, the alternative pathwayfor adipocyte lipid breakdown, lipophagy mightbe an interesting target for treatment. Increasedautophagy, as observed in obese adipose tissue,might be a compensatory mechanism for animpaired classical lipolysis, and contribute to thedevelopment of systemic insulin resistance whenall steps in this pathway are not aligned with eachother (Figure 2). Thus, fine-tuning all three steps inthe autophagy-lysosomal-mitochondrial pathwayin human adipose tissue may be critical regardingtreatment outcome. For this reason, componentswith dual/multiple action on lipid metabolismmight hold promise for future treatment ofcMet disorders.REFERENCES1. Whitlock G et al. Body-mass indexand cause-specific mortality in900,000 adults: collaborative analysesof 57 prospective studies. Lancet.2009;373(9669):1083-96.2. Karastergiou K, Fried SK. Multipleadipose depots increase cardiovascularrisk via local and systemic effects. CurrAtheroscler Rep. 2013;15(10):361.3. Bluher M. Are there still healthy obesepatients? Curr Opin Endocrinol DiabetesObes. 2012;19:341-6.4. Thorne A et al. A pilot study of longtermeffects of a novel obesity treatment:omentectomy in connection withadjustable gastric banding. Int J ObesRelat Metab Disord. 2002;26(2):193-9.5. Lottati M et al. Greater omentectomyimproves insulin sensitivity in nonobesedogs. Obesity (Silver Spring).2009;17(4):674-80.6. Csendes A et al. A prospectiverandomized study comparing patientswith morbid obesity submitted tolaparotomic gastric bypass with or withoutomentectomy. Obes Surg. 2009;19:490-4.7. Klein S et al. Absence of an effect ofliposuction on insulin action and riskfactors for coronary heart disease. N EnglJ Med. 2004;350(25):2549-57.8. Goossens GH. The role of adiposetissue dysfunction in the pathogenesis ofobesity-related insulin resistance. PhysiolBehav. 2008;94:206-18.9. Hellmer J et al. Mechanisms fordifferences in lipolysis between humansubcutaneous and omental fat cells. J ClinEndocrinol Metab. 1992;75:15-20.10. Arner P et al. Beta-adrenoceptorexpression in human fat cells from differentregions. J Clin Invest. 1990;86:1595-600.11. Imbeault P et al. Reduced alpha(2)-adrenergic sensitivity of subcutaneousabdominal adipocytes as a modulatorof fasting and postprandial triglyceridelevels in men. J Lipid Res. 2000;41:1367-75.DIABETES • October 2014 EMJ EUROPEAN MEDICAL JOURNAL 79

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