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Lindsund, Erik
Publications (8 of 8) Show all publications
Lindsund, E. (2023). Dietary, Pharmacological and Environmental Effects on Brown Adipose Tissue. (Doctoral dissertation). Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University
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
von Essen, G., Lindsund, E., Maldonado, E., Zouhar, P., Cannon, B. & Nedergaard, J. (2023). Highly recruited brown adipose tissue does not in itself protect against obesity. Molecular Metabolism, 76, Article ID 101782.
Open this publication in new window or tab >>Highly recruited brown adipose tissue does not in itself protect against obesity
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2023 (English)In: Molecular Metabolism, ISSN 2212-8778, Vol. 76, article id 101782Article in journal (Refereed) Published
Abstract [en]

Objective: The possibility to counteract the development of obesity in humans by recruiting brown or brite/beige adipose tissue (and thus UCP1) has attracted much attention. Here we examine if a diet that can activate diet-induced thermogenesis can exploit pre-enhanced amounts of UCP1 to counteract the development of diet-induced obesity.Methods: To investigate the anti-obesity significance of highly augmented amounts of UCP1 for control of body energy reserves, we physiologically increased total UCP1 amounts by recruitment of brown and brite/beige tissues in mice. We then examined the influence of the augmented UCP1 levels on metabolic parameters when the mice were exposed to a high-fat/high-sucrose diet under thermoneutral conditions.Results: The total UCP1 levels achieved were about 50-fold higher in recruited than in non-recruited mice. Contrary to underlying expectations, in the mice with highly recruited UCP1 and exposed to a high-fat/high-sucrose diet the thermogenic capacity of this UCP1 was completely inactivate. The mice even transiently (in an adipostat-like manner) demonstrated a higher metabolic efficiency and fat gain than did non-recruited mice. This was accomplished without altering energy expenditure or food absorption efficiency. The metabolic efficiency here was indistinguishable from that of mice totally devoid of UCP1.Conclusions: Although UCP1 protein may be available, it is not inevitably utilized for diet-induced thermogenesis. Thus, although attempts to recruit UCP1 in humans may become successful as such, it is only if constant activation of the UCP1 is also achieved that amelioration of obesity development could be attained.& COPY; 2023 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Keywords
Diet-induced thermogenesis, UCP1, Body weight regulation, Beige adipose tissue, Adipostat, Glucose homeostasis
National Category
Clinical Medicine
Identifiers
urn:nbn:se:su:diva-222230 (URN)10.1016/j.molmet.2023.101782 (DOI)001063640000001 ()37499977 (PubMedID)2-s2.0-85167813527 (Scopus ID)
Available from: 2023-10-11 Created: 2023-10-11 Last updated: 2023-10-11Bibliographically approved
Davies, V. S., Lindsund, E., Petrovic, N., Cannon, B. & Nedergaard, J. (2023). Repeated short excursions from thermoneutrality suffice to restructure brown adipose tissue. Biochimie, 210, 40-49
Open this publication in new window or tab >>Repeated short excursions from thermoneutrality suffice to restructure brown adipose tissue
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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
Dittner, C., Lindsund, E., Cannon, B. & Nedergaard, J. (2019). At thermoneutrality, acute thyroxine-induced thermogenesis and pyrexia are independent of UCP1. Molecular Metabolism, 25, 20-34
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
Lindsund, E. (2019). Low Protein Diets and Their Effects on Brown Adipose Tissue. (Licentiate dissertation). Stockholm: Stockholm University
Open this publication in new window or tab >>Low Protein Diets and Their Effects on Brown Adipose Tissue
2019 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Obesity is a rising health issue and has been linked with a relative decrease of dietary protein, which promotes higher food intake.

Brown adipose tissue is a heat-producing, energy-wasting organ that has been shown to be enhanced by a low protein diet. However, the mechanism of how this occurs is largely unknown.

Protein and amino acid concentration are detected biologically by several mechanisms: taste receptors in the tongue and inside the gut secrete many endocrine factors upon feeding, such as CCK, GLP-1 and PYY. GCN2 binds to unbound tRNA instead of the usual binding partner for tRNA: amino acids. Upon low protein feeding, GCN2 alters behaviour in mice and rats and induces many downstream signalling pathways, including FGF21. mTORC1 indirectly detects protein concentration and downregulates protein synthesis and growth when amino acid supply is low.

Animals respond to low protein feeding using many endocrine factors, including CCK, GLP-1, PYY and FGF21, affecting brown fat in various ways. CCK induces hyperthermia, where brown fat can be used as an effector. GLP-1 promotes brown fat via the brain but does not pass the blood-brain barrier. GLP-1 in the periphery may down-regulate brown fat. PYY has been directly linked to promoting lowered food intake when mice are fed a high protein diet. In humans, PYY decreases food intake by causing nausea. PYY has been poorly studied in regards to brown fat. FGF21 is released from the liver when mice are fed a low protein diet and promotes brown fat via the brain. FGF21 could act directly on brown adipose tissue, but a direct effect has only been shown when pharmacological doses are used.

In conclusion; the response to low protein feeding in humans and other animals is complex and uses many varying mechanisms and mediators, including brown adipose tissue.

Place, publisher, year, edition, pages
Stockholm: Stockholm University, 2019. p. 59
Keywords
Obesity, Protein diets, Dietary protein, Brown adipose tissue, Brown fat, BAT, UCP10, Uncoupeling protein 1
National Category
Biological Sciences
Research subject
Molecular Bioscience; Physiology
Identifiers
urn:nbn:se:su:diva-168966 (URN)
Presentation
2019-06-12, Vivi Täckholmssalen, Svante Arrhenius väg 20A, Stockholm, 10:30 (English)
Opponent
Supervisors
Available from: 2019-06-19 Created: 2019-05-21 Last updated: 2022-02-26Bibliographically approved
von Essen, G., Lindsund, E., Cannon, B. & Nedergaard, J. (2017). Adaptive facultative diet-induced thermogenesis in wild-type but not in UCP1-ablated mice. American Journal of Physiology. Endocrinology and Metabolism, 313(5), E515-E527
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
von Essen, G., Lindsund, E., Cannon, B. & Nedergaard, J.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
(English)Manuscript (preprint) (Other academic)
Keywords
Brown adipose tissue, facultative diet-induced thermogenesis, energy expenditure, UCP1, uncoupling protein 1, oxygen consumption, UCP!-ablated, mice
National Category
Biological Sciences Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-140443 (URN)
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2022-02-28Bibliographically approved
von Essen, G., Maldonado, E., Lindsund, E., Cannon, B. & Nedergaard, J.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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