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Dietary, Pharmacological and Environmental Effects on Brown Adipose Tissue
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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 [en]
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: urn:nbn:se:su:diva-214080ISBN: 978-91-8014-172-7 (print)ISBN: 978-91-8014-173-4 (electronic)OAI: oai:DiVA.org:su-214080DiVA, id: diva2:1729922
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
List of papers
1. Adrenergic stimulation as a means to determine in vivo brown adipose tissue thermogenic capacity
Open this publication in new window or tab >>Adrenergic stimulation as a means to determine in vivo brown adipose tissue thermogenic capacity
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Norepinephrine (NE) and the b3-agonist CL 316,423 (CL) have long been used to assess the capacity for non-shivering thermogenesis in intact mice. Here we examine mice with low or high amounts of Uncoupling Protein 1 (UCP1) and compare the effects of injecting NE or CL on energy expenditure, while the mice were awake or anesthetized with pentobarbital. All four conditions tested (awake or anesthetized, injected with NE or with CL) yield significant differences between cold- and thermoneutral-acclimated mice, as well as between wildtype and UCP1 KO mice. The cold acclimation-recruited thermogenesis elicited by CL was not significantly lower than that elicited by norepinephrine, and the level of cold acclimation-recruited adrenergically induced thermogenesis obtained was not affected by anaesthesia. The absence of UCP1 totally (in awake mice) or practically (in anesthetized mice) eliminated the cold acclimation-recruited adrenergically induced thermogenesis. Higher cold acclimation-recruited adrenergically induced thermogenesis correlates positively with UCP1 amount. 

National Category
Biochemistry and Molecular Biology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-214078 (URN)
Available from: 2023-01-23 Created: 2023-01-23 Last updated: 2023-01-23
2. Repeated short excursions from thermoneutrality suffice to restructure brown adipose tissue
Open this publication in new window or tab >>Repeated short excursions from thermoneutrality suffice to restructure brown adipose tissue
Show others...
2023 (English)In: Biochimie, ISSN 0300-9084, E-ISSN 1638-6183, Vol. 210, p. 40-49Article in journal (Refereed) Published
Abstract [en]

Given the presence of brown adipose tissue in adult humans, an important issue is whether human brown adipose tissue is recruitable. Cold exposure is the canonical recruitment treatment; however, in experimental animals (mice), recruitment of brown adipose tissue is normally induced by placing the mice in constant cold, a procedure not feasible in humans. For possible translational applications, we have therefore investigated whether shorter daily excursions from thermoneutrality would suffice to qualitatively and quantitatively induce recruitment in mice. Mice, housed at thermoneutrality (30 °C) to mimic human conditions, were transferred every day for 4 weeks to cool conditions (18 °C), for 0, 15, 30, 120 and 420 min (or placed constantly in 18 °C). On the examination day, the mice were not exposed to cold. Very short daily exposures (≤30 minutes) were sufficient to induce structural changes in the form of higher protein density in brown adipose tissue, changes that may affect the identification of the tissue in e.g. computer tomography and other scan studies. To estimate thermogenic capacity, UCP1 protein levels were followed. No UCP1 protein was detectable in inguinal white adipose tissue. In the interscapular brown adipose tissue, a remarkable two-phase reaction was seen. Very short daily exposures (≤30 minutes) were sufficient to induce a significant increase in total UCP1 levels. For attainment of full cold acclimation, the mice had, however, to remain exposed to the cold. The studies indicate that marked alterations in brown adipose tissue composition can be induced in mammals through relatively modest stimulation events.

National Category
Medical Bioscience
Identifiers
urn:nbn:se:su:diva-214074 (URN)10.1016/j.biochi.2023.01.006 (DOI)36657658 (PubMedID)2-s2.0-85148701823 (Scopus ID)
Available from: 2023-01-23 Created: 2023-01-23 Last updated: 2023-10-12Bibliographically approved
3. Adaptive facultative diet-induced thermogenesis in wild-type but not in UCP1-ablated mice
Open this publication in new window or tab >>Adaptive facultative diet-induced thermogenesis in wild-type but not in UCP1-ablated mice
2017 (English)In: American Journal of Physiology. Endocrinology and Metabolism, ISSN 0193-1849, E-ISSN 1522-1555, Vol. 313, no 5, p. E515-E527Article in journal (Refereed) Published
Abstract [en]

The significance of diet-induced thermogenesis (DIT) for metabolic control is still debated. Although obesogenic diets recruit UCP1 and adrenergically inducible thermogenesis, and although the absence of UCP1 may promote the development of obesity, no actual UCP1-related thermogenesis identifiable as diet-induced thermogenesis has to date been unambiguously demonstrated. Examining mice living at thermoneutrality, we have identified a process of facultative (directly elicited by acute eating), adaptive (magnitude develops over weeks on an obesogenic diet), and fully UCP1-dependent thermogenesis. We found no evidence for UCP1-independent diet-induced thermogenesis. The thermogenesis was proportional to the total amount of UCP1 protein in brown adipose tissue and was not dependent on any contribution of UCP1 in brite/beige adipose tissue, since no UCP1 protein was found there under these conditions. Total UCP1 protein amount developed proportionally to total body fat content. The physiological messenger linking obesity level and acute eating to increased thermogenesis is not known. Thus UCP1-dependent diet-induced thermogenesis limits obesity development during exposure to obesogenic diets but does not prevent obesity as such.

Keywords
brown adipose tissue, diet-induced obesity, diet-induced thermogenesis, UCP1
National Category
Physiology Endocrinology and Diabetes
Identifiers
urn:nbn:se:su:diva-151000 (URN)10.1152/ajpendo.00097.2017 (DOI)000416502900002 ()28679625 (PubMedID)
Available from: 2018-01-11 Created: 2018-01-11 Last updated: 2023-01-23Bibliographically approved
4. At thermoneutrality, acute thyroxine-induced thermogenesis and pyrexia are independent of UCP1
Open this publication in new window or tab >>At thermoneutrality, acute thyroxine-induced thermogenesis and pyrexia are independent of UCP1
2019 (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. 

Keywords
Thyroid hormone, Thermogenesis, UCP1, Hyperthermia, Pyrexia, Fever, Brown adipose tissue
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-170828 (URN)10.1016/j.molmet.2019.05.005 (DOI)000472215300003 ()31151797 (PubMedID)
Available from: 2019-07-29 Created: 2019-07-29 Last updated: 2023-01-23Bibliographically approved
5. Highly recruited brown adipose tissue does not in itself protect against obesity
Open this publication in new window or tab >>Highly recruited brown adipose tissue does not in itself protect against obesity
Show others...
(English)Manuscript (preprint) (Other academic)
Keywords
Brown adipose tissue, UCP1, uncoupling protein 1, UCP!-ablated, mice, cold-recruited, thermoneutrality, high-fat diet, body fat
National Category
Biological Sciences Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-140444 (URN)
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2023-01-23Bibliographically approved

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