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At thermoneutrality, acute thyroxine-induced thermogenesis and pyrexia are independent of UCP1
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.ORCID iD: 0000-0003-2070-1587
Number of Authors: 42019 (English)In: Molecular Metabolism, ISSN 2212-8778, Vol. 25, p. 20-34Article in journal (Refereed) Published
Abstract [en]

Objective: Hyperthyroidism is associated with increased metabolism (thyroid thermogenesis) and elevated body temperature, often referred to as hyperthermia. Uncoupling protein-1 (UCP1) is the protein responsible for nonshivering thermogenesis in brown adipose tissue. We here examine whether UCP1 is essential for thyroid thermogenesis. Methods: We investigated the significance of UCP1 for thyroid thermogenesis by using UCP1-ablated (UCP1 KO) mice. To avoid confounding factors from cold-induced thermogenesis and to approach human conditions, the experiments were conducted at thermoneutrality, and to resemble conditions of endogenous release, thyroid hormone (thyroxine, T4) was injected peripherally. Results: Both short-term and chronic thyroxine treatment led to a marked increase in metabolism that was largely UCP1-independent. Chronic thyroxine treatment led to a 1-2 degrees C increase in body temperature. This increase was also UCP1 -independent and was maintained even at lower ambient temperatures. Thus, it was pyrexia, i.e. a defended increase in body temperature, not hyperthermia. In wildtype mice, chronic thyroxine treatment induced a large relative increase in the total amounts of UCP1 in the brown adipose tissue (practically no UCP1 in brite/beige adipose tissue), corresponding to an enhanced thermogenic response to norepinephrine injection. The increased UCP1 amount had minimal effects on thyroxine-induced thermogenesis and pyrexia. Conclusions: These results establish that thyroid thermogenesis is a UCP1 -independent process. The fact that the increased metabolism coincides with elevated body temperature and thus with accelerated kinetics accentuates the unsolved issue of the molecular background for thyroid thermogenesis. 

Place, publisher, year, edition, pages
2019. Vol. 25, p. 20-34
Keywords [en]
Thyroid hormone, Thermogenesis, UCP1, Hyperthermia, Pyrexia, Fever, Brown adipose tissue
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-170828DOI: 10.1016/j.molmet.2019.05.005ISI: 000472215300003PubMedID: 31151797OAI: oai:DiVA.org:su-170828DiVA, id: diva2:1339376
Available from: 2019-07-29 Created: 2019-07-29 Last updated: 2023-01-23Bibliographically approved
In thesis
1. Dietary, Pharmacological and Environmental Effects on Brown Adipose Tissue
Open this publication in new window or tab >>Dietary, Pharmacological and Environmental Effects on Brown Adipose Tissue
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity is a common health issue; over 12 % of the adult world population have obesity. Obesity has many co-morbidities including cardo-vascular diseases and diabetes. Obesity is the result of chronic positive energy balance, eating too much and expending too little. There are several drugs on the market for treating obesity, but they have limited efficiency and have thus far been unable to halt the current obesity epidemic. All current obesity drugs function by reducing food intake, which is only one half of the energy balance equation, the other being energy expenditure.

The measurement of heat exchange, calorimetry, has a long history, stretching back to the late 18th century. Today most calorimetry on animals uses an indirect method, measuring oxygen consumption and carbon dioxide production. These machines are generally termed respirometers or indirect calorimeters. Already in the late 19th century, it was shown that direct and indirect calorimetry have very close agreement. In animal metabolism carbohydrates, fat and protein, together with oxygen, go through many enzymatic processes, finally resulting in mainly carbon dioxide, water, urea and adenosine triphosphate (ATP). Brown adipose tissue (BAT) can uncouple this process from the final step, ATP production, using the mitochondrial protein uncoupling protein 1 (UCP1), yielding heat.

BAT is a heat-producing organ in many mammals, including humans. Active BAT in adult humans was re-discovered in a metabolic context relatively recently, in 2007, which increased the interest in this field markedly. When activated, BAT has very high energy expenditure per tissue weight. There are currently no safe and comfortable ways to induce BAT recruitment and activation, potentially except for short exposure to moderate cold (II). It is hoped that BAT recruitment and activation may be utilised, in the future, to increase energy expenditure and be used to treat obesity.

In this thesis, I have investigated thyroxine (IV), noradrenaline and a beta-3 selective agonist, CL 316,243 (I). I found that thyroxine recruits BAT, but thyroxine can raise energy expenditure in UCP1-knockout (UCP1-KO) mice as well. I also found that noradrenaline and CL 316,243 both activated BAT, with noradrenaline being slightly more efficient, and injections of these drugs could be used to measure maximum BAT activity in vivo utilising respirometry. I have also determined that as little as 15-minute exposure per day to moderate cold could significantly recruit UCP1 (II).

Diets can also impact BAT. I have investigated the effects of diets high in fat and sugar (HFD) (III; V) on BAT. I found that mice fed these diets increased energy expenditure, especially during mealtime, in a UCP1-dependent manner. Finally, I found that highly recruited UCP1 did not protect against obesity when not activated. Mice with highly recruited, but non-active, UCP1 even transiently gained more weight than mice with non-recruited UCP1.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2023. p. 125
Keywords
Obesity, brown adipose tissue, uncoupling protein 1, moderate cold exposure, calorimetry, thyroxine, dietary protein, thermic effect of food, diet-induced thermogenesis, adrenergic stimulation, mice, physiology
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-214080 (URN)978-91-8014-172-7 (ISBN)978-91-8014-173-4 (ISBN)
Public defence
2023-03-17, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius väg 20, STOCKHOLM, 10:00 (English)
Opponent
Supervisors
Available from: 2023-02-27 Created: 2023-01-23 Last updated: 2023-02-27Bibliographically approved

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Lindsund, ErikCannon, BarbaraNedergaard, Jan

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