Regulation of Energy Homeostasis
Previous and Current Research
Energy homeostasis is a major determinant of health- and life span. While caloric excess leads to insulin resistance, cardiometabolic disease and premature death, caloric restriction prevents and cures these traits. Our group investigates novel regulators of energy, glucose and lipid homeostasis and their impact on insulin resistance, type 2 diabetes, obesity and aging.
Role of INDY (I’m Not Dead Yet) and other SLC Transporters in Metabolic Disease
Reduced expression of the Indy (= I’m Not Dead Yet) gene, which encodes a cell surface transporter for tri- and dicarboxylic acids, prolongs life and health span in a manner akin to caloric restriction in D. melanogaster and C. elegans. In order to test if Indy also effects mammalian metabolism, we generated the Indy knock out mouse (mINDY-/-). Similar to D. melanogaster, mINDY-/- mice mimic a state of caloric restriction with increased mitochondrial biogenesis, hepatic lipid oxidation, and insulin sensitivity. In addition, mINDY-/- mice are protected from the adiposity and insulin resistance that evolves with high-fat feeding and aging.
With our group, we address the question if deletion of the mammalian Indy gene (mIndy) also promotes longevity in mammals and we look for molecular mechanisms explaining the effects of mIndy on metabolism, aging, and life span. We will establish the effects of mIndy in distinct metabolically active tissues in vivo and pinpoint transcriptional regulators of mIndy. In a translational approach, the effect of mIndy on human metabolism and the influence of mINDY’s substrates on mammalian metabolism will be determined. It is our aim to identify new physiological concepts connecting metabolic regulation with aging and longevity and to implement them into innovative pharmacological approaches for the treatment of obesity, insulin resistance, and senescence.
Loeffelholz C, Lieske S, Neuschäfer-Rube F, Willmes DM, Raschzok N, Sauer IM, König J, Fromm M, Horn P, Chatzigeorgiou A, Pathe-Neuschäfer-Rube A, Jordan J, Pfeiffer AFH, Mingrone G, Bornstein SR, Stroehle P, Wunderlich FT, Helfand SL, Bernier M, deCabo R, Shulman GI, Chavakis T, Püschel GP, Birkenfeld AL
The Human Longevity Gene Homolog INDY and Interleukin-6 Interact in Hepatic Lipid Metabolism.
Hepatology, epub (2017)
Schlueter N, de Sterke A, Willmes DM, Spranger J, Jordan J, Birkenfeld AL
Metabolic Actions of Natriuretic Peptides and Therapeutic Potential in the Metabolic Syndrome.
Pharmacol Ther 144:12–27 (2014)
Birkenfeld AL, Shulman GI
Hepatic Non Alcoholic Fatty Liver Disease, Hepatic Insulin Resistance and Type 2 Diabetes.
Hepatology 59(2):713-23 (2014)
Birkenfeld AL, Lee HY, Guebre-Egziabher F, Alves TC, Jurczak MJ, Jornayvaz FR, Zhang D, Hsiao JJ, Martin-Montalvo A, Fischer-Rosinsky A, Spranger J, Pfeiffer AF, Jordan J, Carmean CM, Knauf F, Irusta PM, De Cabo R, Helfand SL, Samuel VT, Shulman GI
Deletion of the Mammalian INDY-Homologue in Mice Mimics Aspects of Dietary Restriction and Protects Against Diet and Age-Induced Adiposity and Insulin Resistance.
Cell Metab 14:185–195 (2011)
Pajvani UB, Shawber CJ, Samuel VT, Birkenfeld AL, Shulman GI, Kitajewski J, Accili D
Inhibition of Notch Signaling Ameliorates Obesity Induced Insulin Resistance Through FoxO1-Dependent Manner.
Nat Med 17:961–967 (2011)