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Thermal physiology and metabolism: Interplay between heat generation and energy homeostasis
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. (Nedergaard)
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: urn:nbn:se:su:diva-115874ISBN: 978-91-7649-156-0 (print)OAI: oai:DiVA.org:su-115874DiVA: diva2:800524
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
List of papers
1. Adrenergically-stimulated blood flow in brown adipose tissue is not dependent on thermogenesis: Regulation of brown adipose tissue blood flow
Open this publication in new window or tab >>Adrenergically-stimulated blood flow in brown adipose tissue is not dependent on thermogenesis: Regulation of brown adipose tissue blood flow
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2015 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 308, no 9, E822-E829 p.Article in journal (Refereed) Published
Abstract [en]

Brown adipose tissue (BAT) thermogenesis relies on blood flow to be supplied with nutrients and oxygen, and for the distribution of the generated heat to the rest of the body. It is therefore fundamental to understand the mechanisms by which blood flow is regulated and its relation to thermogenesis. Here we present high-resolution laser-Doppler imaging (HR-LDR) as a novel method for noninvasive, in vivo measurement of BAT blood flow in mice. Using HR-LDR, we found that norepinephrine stimulation increases BAT blood flow in a dose-dependent manner, and that this response is profoundly modulated by environmental temperature acclimation. Surprisingly, we found that mice lacking uncoupling protein 1 (UCP1) have fully preserved BAT blood flow response to norepinephrine, despite failing to perform thermogenesis. BAT blood flow was not directly correlated to systemic glycaemia, but glucose injections could transiently increase tissue perfusion. Inguinal white adipose tissue, also known as a brite/beige adipose tissue, was also sensitive to cold acclimation and similarly increased blood flow in response to norepinephrine. In conclusion, using a novel non-invasive method to detect BAT perfusion, we demonstrate that adrenergically-stimulated BAT blood flow is qualitatively and quantitatively fully independent of thermogenesis, and is therefore not a reliable parameter for the estimation of BAT activation and heat generation.

Keyword
blood flow, brown adipose tissue, high-resolution laser-Doppler imaging, thermogenesis, uncoupling protein 1
National Category
Biological Sciences
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-115869 (URN)10.1152/ajpendo.00494.2014 (DOI)000353951700011 ()
Available from: 2015-04-06 Created: 2015-04-06 Last updated: 2017-12-04Bibliographically approved
2. Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-3
Open this publication in new window or tab >>Regulation of body temperature and brown adipose tissue thermogenesis by bombesin receptor subtype-3
2014 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 306, no 6, E681-E687 p.Article in journal (Refereed) Published
Abstract [en]

Bombesin receptor subtype-3 (BRS-3) regulates energy homeostasis, with Brs3 knockout (Brs3(-/y)) mice being hypometabolic, hypothermic, and hyperphagic and developing obesity. We now report that the reduced body temperature is more readily detected if body temperature is analyzed as a function of physical activity level and light/dark phase. Physical activity level correlated best with body temperature 4 min later. The Brs3(-/y) metabolic phenotype is not due to intrinsically impaired brown adipose tissue function or in the communication of sympathetic signals from the brain to brown adipose tissue, since Brs3(-/y) mice have intact thermogenic responses to stress, acute cold exposure, and beta 3-adrenergic activation, and Brs3(-/y) mice prefer a cooler environment. Treatment with the BRS-3 agonist MK-5046 increased brown adipose tissue temperature and body temperature in wild-type but not Brs3(-/y) mice. Intrahypothalamic infusion of MK5046 increased body temperature. These data indicate that the BRS-3 regulation of body temperature is via a central mechanism, upstream of sympathetic efferents. The reduced body temperature in Brs3(-/y) mice is due to altered regulation of energy homeostasis affecting higher center regulation of body temperature, rather than an intrinsic defect in brown adipose tissue.

Keyword
bombesin receptor subtype-3, obesity, sympathetic nervous system, brown adipose tissue, thermoregulation, CL316243, MK-5046
National Category
Biological Sciences
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-102966 (URN)10.1152/ajpendo.00615.2013 (DOI)000333332700010 ()
Note

AuthorCount:4;

Available from: 2014-04-29 Created: 2014-04-25 Last updated: 2017-12-05Bibliographically approved
3. Integration of body temperature into the analysis of energy expenditure in the mouse
Open this publication in new window or tab >>Integration of body temperature into the analysis of energy expenditure in the mouse
2015 (English)In: Molecular Metabolism, ISSN 2212-8778, Vol. 4, no 6, 461-470 p.Article in journal (Refereed) Published
Abstract [en]

Objectives: We quantified the effect of environmental temperature on mouse energy homeostasis and body temperature.Methods: The effect of environmental temperature (4e33 C) on body temperature, energy expenditure, physical activity, and food intake invarious mice (chow diet, high-fat diet, Brs3-/y, lipodystrophic) was measured using continuous monitoring.Results: Body temperature depended most on circadian phase and physical activity, but also on environmental temperature. The amounts ofenergy expenditure due to basal metabolic rate (calculated via a novel method), thermic effect of food, physical activity, and cold-inducedthermogenesis were determined as a function of environmental temperature. The measured resting defended body temperature matchedthat calculated from the energy expenditure using Fourier’s law of heat conduction. Mice defended a higher body temperature during physicalactivity. The cost of the warmer body temperature during the active phase is 4e16% of total daily energy expenditure. Parameters measured indiet-induced obese and Brs3-/y mice were similar to controls. The high post-mortem heat conductance demonstrates that most insulation in miceis via physiological mechanisms.Conclusions: At 22 C, cold-induced thermogenesis isw120% of basal metabolic rate. The higher body temperature during physical activity isdue to a higher set point, not simply increased heat generation during exercise. Most insulation in mice is via physiological mechanisms, with littlefrom fur or fat. Our analysis suggests that the definition of the upper limit of the thermoneutral zone should be re-considered. Measuring bodytemperature informs interpretation of energy expenditure data and improves the predictiveness and utility of the mouse to model human energyhomeostasis.

Keyword
Thermoneutrality, Basal metabolic rate, Cold-induced thermogenesis, Body temperature, Energy expenditure, Heat conductance
National Category
Biochemistry and Molecular Biology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-115870 (URN)10.1016/j.molmet.2015.03.001 (DOI)000367439600002 ()
Available from: 2015-04-06 Created: 2015-04-06 Last updated: 2016-02-01Bibliographically approved
4. On adequate procedures for glucose tolerance tests in obese animals: Measurement of glucose tolerance in obesity
Open this publication in new window or tab >>On adequate procedures for glucose tolerance tests in obese animals: Measurement of glucose tolerance in obesity
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Routine procedures for glucose tolerance test in rodents utilize an amount of injected glucose that is proportional to total body weight (normally 2 mg per g body weight). Obese mice consist of much more chemically inert lipid than lean mice but have only marginal increases in lean body mass (the only compartment where glucose is distributed). Present procedures thus inevitably lead to a diagnosis of impaired glucose tolerance and enhanced insulin levels in obesity. Routine procedures should use fixed glucose amounts per lean body mass (or per mouse).

National Category
Biological Sciences
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-115871 (URN)
Available from: 2015-04-06 Created: 2015-04-06 Last updated: 2016-01-29Bibliographically approved
5. Cidea improves the metabolic profile through expansion of adipose tissue
Open this publication in new window or tab >>Cidea improves the metabolic profile through expansion of adipose tissue
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2015 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, 7433Article in journal (Refereed) Published
Abstract [en]

In humans, Cidea (cell death-inducing DNA fragmentation factor alpha-like effector A) is highly but variably expressed in white fat, and expression correlates with metabolic health. Here we generate transgenic mice expressing human Cidea in adipose tissues (aP2-hCidea mice) and show that Cidea is mechanistically associated with a robust increase in adipose tissue expandability. Under humanized conditions (thermoneutrality, mature age and prolonged exposure to high-fat diet), aP2-hCidea mice develop a much more pronounced obesity than their wild-type littermates. Remarkably, the malfunctioning of visceral fat normally caused by massive obesity is fully overcome-perilipin 1 and Akt expression are preserved, tissue degradation is prevented, macrophage accumulation is decreased and adiponectin expression remains high. Importantly, the aP2-hCidea mice display enhanced insulin sensitivity. Our data establish a functional role for Cidea and suggest that, in humans, the association between Cidea levels in white fat and metabolic health is not only correlative but also causative.

National Category
Cell Biology Cell and Molecular Biology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-119248 (URN)10.1038/ncomms8433 (DOI)000357176500005 ()
Available from: 2015-08-14 Created: 2015-08-03 Last updated: 2017-12-04Bibliographically approved
6. Novel thiazolidinediones distinguish between (UCP1-independent) antidiabetic effects (MSDC-0602) and adipogenic and browning-inducing effects (MSDC-0160) of classical thiazolidinediones (rosiglitazone)
Open this publication in new window or tab >>Novel thiazolidinediones distinguish between (UCP1-independent) antidiabetic effects (MSDC-0602) and adipogenic and browning-inducing effects (MSDC-0160) of classical thiazolidinediones (rosiglitazone)
(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:nbn:se:su:diva-115873 (URN)
Available from: 2015-04-06 Created: 2015-04-06 Last updated: 2016-01-29Bibliographically approved

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