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Novel thiazolidinediones distinguish between (UCP1-independent) antidiabetic effects (MSDC-0602) and adipogenic and browning-inducing effects (MSDC-0160) of classical thiazolidinediones (rosiglitazone)
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Thiazolinediones (TZDs), also called glitazones, are a class of drugs traditionally used forimproving glucose tolerance in type II diabetes mellitus. The beneficial effects ofthiazolidinedione are believed to be caused by the drug binding to the nuclear receptor PPARγ,which in turn triggers a general adipogenic program in white adipose tissue, and apparentthermogenic recruitment of brown and brite/beige fat. Here, we present a comparison of thephysiological effects of three thiazolidinediones (rosiglitazone, MSDC-0602, and MSDC-0160)in C57BL/6 mice fed high-fat diet and housed at thermoneutrality. Rosiglitazone and MSDC-0160 caused the classically-described thiazolidinedione effects of increased fat mass,hyperphagia, and increased UCP1 levels in brown adipose tissue. MSDC-0602 and rosiglitazoneimproved glucose tolerance but MSDC-0602 did not induce increased fat mass, hyperphagia, orincreased UCP1 levels in brown fat. The beneficial effects of thiazolidinediones were fullypresent even in UCP1-KO mice, providing evidence for a dissociation between thiazolidinedioneinducedadipose tissue browning and their antidiabetic effects. We conclude that even structurallysimilar thiazolidinediones can act through distinct pathways, and that the glucose-loweringeffects of this class do not seem to rely on PPAR-γ-induced browning of adipose tissues.

National Category
Medical and Health Sciences
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-115873OAI: oai:DiVA.org:su-115873DiVA: diva2:800516
Available from: 2015-04-06 Created: 2015-04-06 Last updated: 2016-01-29Bibliographically approved
In thesis
1. Thermal physiology and metabolism: Interplay between heat generation and energy homeostasis
Open this publication in new window or tab >>Thermal physiology and metabolism: Interplay between heat generation and energy homeostasis
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mammal metabolism is intimately connected to the maintenance of body temperature. While metabolic pathways invariably produce heat as a by-product, the natural heat present in the environment also plays a role in defining the adaptive metabolism and general physiology of an organism. This thesis aims to discuss basic aspects of energy expenditure and their interactions with energy stores and body composition. In Paper I, we apply a new technique – high-resolution laser-Doppler imaging – to describe physiological regulatory features of adrenergically-stimulated blood flow in brown adipose tissue, and evaluate the validity of blood flow as a parameter to estimate nonshivering thermogenesis. Paper II focuses on the central regulation of body temperature. In the absence of bombesin receptor subtype-3, mice present an altered neurological body temperature setpoint, while peripheral thermogenic capacity remains intact. We conclude that brown adipose tissue malfunction is not the cause of the hypothermia observed in this mouse model. Paper III incorporates measurements of body temperature to the energy expenditure of different sources: basal metabolic rate, physical activity, thermic effect of food, and cold-induced thermogenesis. We describe basic aspects of dynamic insulation, energetic costs of circadian variation and hypothesize that physical activity may change the body temperature setpoint. Paper IV describes methodological issues related to glucose tolerance tests in obese mice. We conclude that the erroneous scaling of doses may affect the interpretation of metabolic health in mouse models, and suggest a new methodology. Paper V describes the outcomes caused by the expression of the human Cidea protein in adipose tissue of mice and suggests that this protein may clarify the link between adipose tissue expansion and healthy obesity. Paper VI explores the dissociation between thiazolidinedione-induced adipose tissue “browning” and reduced blood glycaemia. We demonstrate that although this pharmacological class tends to induce some level of brown adipose tissue recruitment, this phenomenon does not define its antidiabetic effects.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2015. 55 p.
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-115874 (URN)978-91-7649-156-0 (ISBN)
Public defence
2015-05-13, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 4: Manuscript. Paper 5: Manuscript. Paper 6: Manuscript.

Available from: 2015-04-20 Created: 2015-04-06 Last updated: 2017-03-28Bibliographically approved

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Abreu-Vieira, GustavoKalinovich, AnastasiaCannon, BarbaraNedergaard, Jan
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