TY - BOOK

T1 - Brown adipocyte function

T2 - A study of signaling and fuel pathways

AU - Winther, Sally

PY - 2017

Y1 - 2017

N2 - The global increase in obesity and its associated metabolic complications such as type II diabetesis a major concern for the public health. Current pharmaceutical obesity interventionsare few and often have limited efficacy. An interesting target for obesity treatment is increasingenergy expenditure. Brown adipose tissue (BAT) has the ability to dissipate energy asheat in the process of non-shivering thermogenesis. This unique feature of BAT is conferredby the presence of the mitochondrial uncoupling protein 1, which can disengage the mitochondrialproton gradient from ATP production releasing the stored energy as heat. Physiologicallythe process is activated by cold exposure but can also be mimicked by stimulationwith β-adrenergic agonists.Finding specific inducers of BAT activity requires detailed knowledge of the signaling cascadesgoverning β-adrenergic stimulated thermogenesis. The first part of this thesis exploresthis by identifying and investigating two novel kinase regulators of brown adipocyte function.Study 1 demonstrates that spleen tyrosine kinase is a hitherto undescribed regulator of brownadipocyte differentiation and activation. Study 2 identifies glycogen synthase kinase 3 as anegative regulator of the canonical p38 mitogen-activated protein kinase signaling cascade.Thus both studies add novel regulatory layers to the growing understanding of brown adipocytesignal transduction.Activated BAT also exerts great influence on whole body glucose homeostasis, of great interestfor diabetes treatment. The second part of this thesis explores this by investigating glycolyticflux in activated brown adipocytes. Study 3 identifies hypoxia-inducible factor 1α as animportant regulator of glycolytic gene expression in brown adipocytes. Study 4 establishesthat glycolytic flux is important for β-adrenergically induced oxygen consumption, and highlightsthat glucose oxidation serves multiple purposes in brown adipocytes. Together the studiesdescribe novel aspects of glucose consumption adding to the understanding of substrateoxidation in activated brown adipocytes. Taken together the research presented in this thesisdescribes novel aspects of BAT physiology, adding to the growing understanding of brownadipocyte activation and fuel preferences.

AB - The global increase in obesity and its associated metabolic complications such as type II diabetesis a major concern for the public health. Current pharmaceutical obesity interventionsare few and often have limited efficacy. An interesting target for obesity treatment is increasingenergy expenditure. Brown adipose tissue (BAT) has the ability to dissipate energy asheat in the process of non-shivering thermogenesis. This unique feature of BAT is conferredby the presence of the mitochondrial uncoupling protein 1, which can disengage the mitochondrialproton gradient from ATP production releasing the stored energy as heat. Physiologicallythe process is activated by cold exposure but can also be mimicked by stimulationwith β-adrenergic agonists.Finding specific inducers of BAT activity requires detailed knowledge of the signaling cascadesgoverning β-adrenergic stimulated thermogenesis. The first part of this thesis exploresthis by identifying and investigating two novel kinase regulators of brown adipocyte function.Study 1 demonstrates that spleen tyrosine kinase is a hitherto undescribed regulator of brownadipocyte differentiation and activation. Study 2 identifies glycogen synthase kinase 3 as anegative regulator of the canonical p38 mitogen-activated protein kinase signaling cascade.Thus both studies add novel regulatory layers to the growing understanding of brown adipocytesignal transduction.Activated BAT also exerts great influence on whole body glucose homeostasis, of great interestfor diabetes treatment. The second part of this thesis explores this by investigating glycolyticflux in activated brown adipocytes. Study 3 identifies hypoxia-inducible factor 1α as animportant regulator of glycolytic gene expression in brown adipocytes. Study 4 establishesthat glycolytic flux is important for β-adrenergically induced oxygen consumption, and highlightsthat glucose oxidation serves multiple purposes in brown adipocytes. Together the studiesdescribe novel aspects of glucose consumption adding to the understanding of substrateoxidation in activated brown adipocytes. Taken together the research presented in this thesisdescribes novel aspects of BAT physiology, adding to the growing understanding of brownadipocyte activation and fuel preferences.

UR - https://soeg.kb.dk/permalink/45KBDK_KGL/fbp0ps/alma99122983108305763

M3 - Ph.D. thesis

BT - Brown adipocyte function

PB - Department of Biology, Faculty of Science, University of Copenhagen

ER -