Publications by authors named "Barbara Cannon"

108 Publications

Thermogenic recruitment of brown and brite/beige adipose tissues is not obligatorily associated with macrophage accretion or attrition.

Am J Physiol Endocrinol Metab 2020 Dec 7. Epub 2020 Dec 7.

Cold- and diet-induced recruitment of brown adipose tissue (BAT) and the browning of white adipose tissue (WAT) are dynamic processes, and the recruited state attained is a state of dynamic equilibrium, demanding continuous stimulation to be maintained. An involvement of macrophages, classical pro-inflammatory (M1) or alternatively activated anti-inflammatory (M2), is presently discussed as being an integral part of these processes. If these macrophages play a mediatory role in the recruitment process, such an involvement would have to be maintained in the recruited state. We have therefore investigated whether the recruited state of these tissues is associated with macrophage accretion or attrition. We found no correlation (positive or negative) between total UCP1 mRNA levels (as a measure of recruitment) and pro-inflammatory macrophages in any adipose depot. We found that in young chow-fed mice, cold-induced recruitment correlated with accretion of anti-inflammatory macrophages; however, such a correlation was not seen when cold-induced recruitment was studied in diet-induced obese mice. Further, the anti-inflammatory macrophage accretion was mediated via β/β-adrenergic receptors; yet, in their absence, and thus in the absence of macrophage accretion, recruitment proceeded normally. We thus conclude that the classical recruited state in BAT and inguinal (brite/beige) WAT is not paralleled by macrophage accretion or attrition. Our results make mediatory roles for macrophages in the recruitment process less likely.
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http://dx.doi.org/10.1152/ajpendo.00352.2020DOI Listing
December 2020

Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice.

Nat Metab 2019 08 19;1(8):830-843. Epub 2019 Aug 19.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 °C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.
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http://dx.doi.org/10.1038/s42255-019-0101-4DOI Listing
August 2019

Reply to 'Confounding issues in the 'humanized' brown fat of mice'.

Nat Metab 2020 04 13;2(4):305-306. Epub 2020 Apr 13.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

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http://dx.doi.org/10.1038/s42255-020-0193-xDOI Listing
April 2020

Human brown adipose tissue: Classical brown rather than brite/beige?

Exp Physiol 2020 08 30;105(8):1191-1200. Epub 2020 May 30.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

New Findings: What is the topic of this review? It has been suggested that human brown adipose tissue (BAT) is more similar to the brite/beige adipose tissue of mice than to classical BAT of mice. The basis of this is discussed in relationship to the physiological conditions of standard experimental mice. What advances does it highlight? We highlight that, provided mouse adipose tissues are examined under physiological conditions closer to those prevalent for most humans, the gene expression profile of mouse classical BAT is more similar to that of human BAT than is the profile of mouse brite/beige adipose tissue. Human BAT is therefore not different in nature from classical mouse BAT.

Abstract: Since the presence of brown adipose tissue (BAT) was established in adult humans some 13 years ago, its physiological significance and molecular characteristics have been discussed. In particular, it has been proposed that the mouse adipose tissue depot most closely resembling and molecularly parallel to human BAT is not classical mouse BAT. Instead, so-called brite or beige adipose tissue, which is characteristically observed in the inguinal 'white' adipose tissue depot of mice, has been proposed to be the closest mouse equivalent of human BAT. We summarize here the published evidence examining this question. We emphasize the differences in tissue appearance and tissue transcriptomes from 'standard' mice [young, chow fed and, in effect semi-cold exposed (20°C)] versus 'physiologically humanized' mice [middle-aged, high-fat diet-fed mice living at thermoneutrality (30°C)]. We find that in the physiologically humanized mice, classical BAT displays molecular and cellular characteristics that are more akin to human BAT than are those of brite/beige adipose tissues from either standard or physiologically humanized mice. We suggest, therefore, that mouse BAT is the more relevant tissue for translational studies. This is an invited summary of a presentation given at Physiology 2019 (Aberdeen).
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http://dx.doi.org/10.1113/EP087875DOI Listing
August 2020

Leptin: Is It Thermogenic?

Endocr Rev 2020 04;41(2)

Department of Molecular Biosciences, The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, Stockholm, Sweden.

Animals that lack the hormone leptin become grossly obese, purportedly for 2 reasons: increased food intake and decreased energy expenditure (thermogenesis). This review examines the experimental evidence for the thermogenesis component. Analysis of the data available led us to conclude that the reports indicating hypometabolism in the leptin-deficient ob/ob mice (as well as in the leptin-receptor-deficient db/db mice and fa/fa rats) derive from a misleading calculation artefact resulting from expression of energy expenditure per gram of body weight and not per intact organism. Correspondingly, the body weight-reducing effects of leptin are not augmented by enhanced thermogenesis. Congruent with this, there is no evidence that the ob/ob mouse demonstrates atrophied brown adipose tissue or diminished levels of total UCP1 mRNA or protein when the ob mutation is studied on the inbred C57BL/6 mouse background, but a reduced sympathetic nerve activity is observed. On the outbred "Aston" mouse background, brown adipose tissue atrophy is seen, but whether this is of quantitative significance for the development of obesity has not been demonstrated. We conclude that leptin is not a thermogenic hormone. Rather, leptin has effects on body temperature regulation, by opposing torpor bouts and by shifting thermoregulatory thresholds. The central pathways behind these effects are largely unexplored.
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http://dx.doi.org/10.1210/endrev/bnz016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021639PMC
April 2020

UCP1-independent glucose-lowering effect of leptin in type 1 diabetes: only in conditions of hypoleptinemia.

Am J Physiol Endocrinol Metab 2020 01 19;318(1):E72-E86. Epub 2019 Nov 19.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity - and thus also leptin levels - in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.
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http://dx.doi.org/10.1152/ajpendo.00253.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985793PMC
January 2020

No insulating effect of obesity, neither in mice nor in humans.

Am J Physiol Endocrinol Metab 2019 11;317(5):E952-E953

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

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http://dx.doi.org/10.1152/ajpendo.00333.2019DOI Listing
November 2019

Regulation of thermogenic capacity in brown and white adipocytes by the prebiotic high-esterified pectin and its postbiotic acetate.

Int J Obes (Lond) 2020 03 29;44(3):715-726. Epub 2019 Aug 29.

Laboratory of Molecular Biology, Nutrition and Biotechnology (Nutrigenomics), University of the Balearic Islands (UIB) and CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Palma de Mallorca, 07122, Spain.

Objectives: High-esterified pectin (HEP) is a prebiotic able to modulate gut microbiota, associated with health-promoting metabolic effects in glucose and lipid metabolism and adipostatic hormone sensitivity. Possible effects regulating adaptive thermogenesis and energy waste are poorly known. Therefore, we aimed to study how physiological supplementation with HEP is able to affect microbiota, energy metabolism and adaptive thermogenic capacity, and to contribute to the healthier phenotype promoted by HEP supplementation, as previously shown. We also attempted to decipher some of the mechanisms involved in the HEP effects, including in vitro experiments.

Subjects And Experimental Design: We used a model of metabolic malprogramming consisting of the progeny of rats with mild calorie restriction during pregnancy, both under control diet and an obesogenic (high-sucrose) diet, supplemented with HEP, combined with in vitro experiments in primary cultured brown and white adipocytes treated with the postbiotic acetate.

Results: Our main findings suggest that chronic HEP supplementation induces markers of brown and white adipose tissue thermogenic capacity, accompanied by a decrease in energy efficiency, and prevention of weight gain under an obesogenic diet. We also show that HEP promotes an increase in beneficial bacteria in the gut and peripheral levels of acetate. Moreover, in vitro acetate can improve adipokine production, and increase thermogenic capacity and browning in brown and white adipocytes, respectively, which could be part of the protection mechanism against excess weight gain observed in vivo.

Conclusion: HEP and acetate stand out as prebiotic/postbiotic active compounds able to modulate both brown-adipocyte metabolism and browning and protect against obesity.
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http://dx.doi.org/10.1038/s41366-019-0445-6DOI Listing
March 2020

Glucocorticoids and Brown Adipose Tissue: Do glucocorticoids really inhibit thermogenesis?

Mol Aspects Med 2019 08 27;68:42-59. Epub 2019 Jul 27.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden. Electronic address:

A reduction in the thermogenic activity of brown adipose tissue (BAT) is presently discussed as a possible determinant for the development of obesity in humans. One group of endogenous factors that could potentially affect BAT activity is the glucocorticoids (e.g. cortisol). We analyse here studies examining the effects of alterations in glucocorticoid signaling on BAT recruitment and thermogenic capacity. We find that irrespective of which manipulation of glucocorticoid signaling is examined, a seemingly homogeneous picture of lowered thermogenic capacity due to glucocorticoid stimulation is apparently obtained: e.g. lowered uncoupling protein 1 (UCP1) protein levels per mg protein, and an increased lipid accumulation in BAT. However, further analyses generally indicate that these effects result from a dilution effect rather than a true decrease in total capacity; the tissue may thus be said to be in a state of pseudo-atrophy. However, under conditions of very low physiological stimulation of BAT, glucocorticoids may truly inhibit Ucp1 gene expression and consequently lower total UCP1 protein levels, but the metabolic effects of this reduction are probably minor. It is thus unlikely that glucocorticoids affect organismal metabolism and induce the development of obesity through alterations of BAT activity.
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http://dx.doi.org/10.1016/j.mam.2019.07.002DOI Listing
August 2019

The answer to the question "What is the best housing temperature to translate mouse experiments to humans?" is: thermoneutrality.

Mol Metab 2019 08 18;26:1-3. Epub 2019 May 18.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.molmet.2019.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667698PMC
August 2019

At thermoneutrality, acute thyroxine-induced thermogenesis and pyrexia are independent of UCP1.

Mol Metab 2019 07 26;25:20-34. Epub 2019 May 26.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden. Electronic address:

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 °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.
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http://dx.doi.org/10.1016/j.molmet.2019.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601127PMC
July 2019

Glucocorticoid-Induced Obesity Develops Independently of UCP1.

Cell Rep 2019 05;27(6):1686-1698.e5

Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, 106 91 Stockholm, Sweden. Electronic address:

An excess of glucocorticoids leads to the development of obesity in both mice and humans, but the mechanism for this is unknown. Here, we determine the extent to which decreased BAT thermogenic capacity (as a result of glucocorticoid treatment) contributes to the development of obesity. Contrary to previous suggestions, we show that only in mice housed at thermoneutrality (30°C) does corticosterone treatment reduce total BAT UCP1 protein. This reduction is reflected in reduced brown adipocyte cellular and mitochondrial UCP1-dependent respiration. However, glucocorticoid-induced obesity develops to the same extent in animals housed at 21°C and 30°C, whereas total BAT UCP1 protein levels differ 100-fold between the two groups. In corticosterone-treated wild-type and UCP1 knockout mice housed at 30°C, obesity also develops to the same extent. Thus, our results demonstrate that the development of glucocorticoid-induced obesity is not caused by a decreased UCP1-dependent thermogenic capacity.
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http://dx.doi.org/10.1016/j.celrep.2019.04.041DOI Listing
May 2019

In the absence of UCP1-mediated diet-induced thermogenesis, obesity is augmented even in the obesity-resistant 129S mouse strain.

Am J Physiol Endocrinol Metab 2019 05 26;316(5):E729-E740. Epub 2019 Feb 26.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , Stockholm , Sweden.

The attractive tenet that recruitment and activation of brown adipose tissue (BAT) and uncoupling protein 1 (UCP1) could counteract the development of obesity and its comorbidities in humans has been experimentally corroborated mainly by experiments demonstrating that UCP1-ablated mice on a C57Bl/6 background (exempt from thermal stress) become more obese when fed a high-fat diet. However, concerns may be raised that this outcome of UCP1 ablation is restricted to this very special inbred and particularly obesity-prone mouse strain. Therefore, we have examined to which degree UCP1 ablation has similar metabolic effects in a mouse strain known to be obesity resistant: the 129S strain. For this, male 129S2/sv or 129SV/Pas mice and corresponding UCP1-knockout mice were fed chow or a high-fat or a cafeteria diet for 4 wk. The absence of UCP1 augmented obesity (weight gain, body fat mass, %body fat, fat depot size) in high-fat diet- and cafeteria-fed mice, with a similar or lower food intake, indicating that, when present, UCP1 indeed decreases metabolic efficiency. The increased obesity was due to a decrease in energy expenditure. The consumption of a high-fat or cafeteria diet increased total BAT UCP1 protein levels in wild-type mice, and correspondingly, high-fat diet and cafeteria diet-fed mice demonstrated increased norepinephrine-induced oxygen consumption. There was a positive correlation between body fat and total BAT UCP1 protein content. No evidence for diet-induced adrenergic thermogenesis was found in UCP1-ablated mice. Thus, the obesity-reducing effect of UCP1 is not restricted to a particular, and perhaps not representative, mouse strain.
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http://dx.doi.org/10.1152/ajpendo.00020.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580168PMC
May 2019

Intact innervation is essential for diet-induced recruitment of brown adipose tissue.

Am J Physiol Endocrinol Metab 2019 03 21;316(3):E487-E503. Epub 2018 Dec 21.

Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University , Stockholm , Sweden.

The possibility that recruitment and activation of brown adipose tissue (BAT) thermogenesis could be beneficial for curtailing obesity development in humans prompts a need for a better understanding of the control of these processes [that are often referred to collectively as diet-induced thermogenesis (DIT)]. Dietary conditions are associated with large changes in blood-borne factors that could be responsible for BAT recruitment, but BAT is also innervated by the sympathetic nervous system. To examine the significance of the innervation for DIT recruitment, we surgically denervated the largest BAT depot, i.e., the interscapular BAT depot in mice and exposed the mice at thermoneutrality to a high-fat diet versus a chow diet. Denervation led to an alteration in feeding pattern but did not lead to enhanced obesity, but obesity was achieved with a lower food intake, as denervation increased metabolic efficiency. Conclusively, denervation totally abolished the diet-induced increase in total UCP1 protein levels observed in the intact mice, whereas basal UCP1 expression was not dependent on innervation. The denervation of interscapular BAT did not discernably hyper-recruit other BAT depots, and no UCP1 protein could be detected in the principally browning-competent inguinal white adipose tissue depot under any of the examined conditions. We conclude that intact innervation is essential for diet-induced thermogenesis and that circulating factors cannot by themselves initiate recruitment of brown adipose tissue under obesogenic conditions. Therefore, the processes that link food intake and energy storage to activation of the nervous system are those of significance for the further understanding of diet-induced thermogenesis.
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http://dx.doi.org/10.1152/ajpendo.00443.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459298PMC
March 2019

Brown adipose tissue as a heat-producing thermoeffector.

Handb Clin Neurol 2018 ;156:137-152

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

Extra heat for defense of body temperature can be obtained from shivering or nonshivering thermogenesis. Nonshivering thermogenesis is a facultative (i.e., only occurring when needed) and adaptive (i.e., being augmented when the demand is chronically higher) process that, in mammals, is the result of the activity of uncoupling protein-1 (UCP1) in brown and brownish adipose tissues; no other quantitatively significant mechanism that fulfills the above criteria has been established. Measurement of heat production is generally indirect, based on oxygen consumption. Heat from brown adipose tissue is generated in mammals adapted to cold, in mammalian neonates, and in mammalian hibernators during arousal; brown adipose tissue may also be active in obese mammals and thus partially protect against further obesity. UCP1 is innately inhibited by cytosolic adenosine triphosphate (ATP) and is likely activated by fatty acids released from triglycerides within the cells; this lipolysis is stimulated by norepinephrine released from the sympathetic nerves innervating the tissue. For prolonged thermogenesis, substrate is delivered by the circulation as chylomicrons, lipoproteins, fatty acids, and glucose. The proton gradient over the mitochondrial membrane created by the respiratory chain is dispersed through the activity of UCP1; brown adipose tissue is nearly devoid of ATP synthase (as compared to respiratory chain activity). UCP1 developed likely at the dawn of mammalian evolution; most mammalian species still retain functional UCP1. Other members of the uncoupling protein family cannot uncouple. Both newborn and adult humans possess active brown adipose tissue but the significance of the tissue for adult human metabolism is not established.
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http://dx.doi.org/10.1016/B978-0-444-63912-7.00009-6DOI Listing
March 2019

Promotion of lipid storage rather than of thermogenic competence by fetal versus newborn calf serum in primary cultures of brown adipocytes.

Adipocyte 2018 16;7(3):166-179. Epub 2018 Jul 16.

a Department of Molecular Biosciences , The Wenner-Gren Institute, Stockholm University , Stockholm , Sweden.

Much current understanding of brown adipocyte development comes from in-vitro cell models. Serum type may affect the behavior of cultured cells and thus conclusions drawn. Here, we investigate effects of serum type ("fetal bovine" versus "newborn calf") on responses to differentiation inducers (the PPARγ agonist rosiglitazone or the neurotransmitter norepinephrine) in cultured primary brown adipocytes. Lipid storage was enhanced by fetal versus newborn serum. However, molecular adipose conversion (Pparg2 and Fabp4 expression) was not affected by serum type. Rosiglitazone-induced (7-days) expression of thermogenic genes (i.e. Ucp1, Pgc1a, Dio2 and Elovl3) was not systematically affected by serum type. However, importantly, acute (2 h) norepinephrine-induced thermogenic gene expression was overall markedly higher (and adipose genes somewhat lower) in cells cultured in newborn serum. Thus, newborn serum promotes thermogenic competence, and the use of fetal serum in brown adipocyte cultures (as is often routine) counteracts adequate differentiation. Agents that counteract this inhibition may therefore confoundingly be ascribed genuine thermogenic competence-inducing properties.
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http://dx.doi.org/10.1080/21623945.2018.1479578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224186PMC
September 2019

Cell proliferation and apoptosis inhibition: essential processes for recruitment of the full thermogenic capacity of brown adipose tissue.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 01 14;1864(1):51-58. Epub 2018 Jun 14.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

In mice living under normal animal house conditions, the brown adipocytes in classical brown adipose tissue depots are already essentially fully differentiated: UCP1 mRNA and UCP1 protein levels are practically saturated. This means that any further recruitment - in response to cold exposure or any other browning agent - does not result in significant augmentation of these parameters. This may easily be construed to indicate that classical brown adipose tissue cannot be further recruited. However, this is far from the case: the capacity for further recruitment instead lies in the ability of the tissue to increase the number of brown-fat cells, a remarkable and highly controlled physiological recruitment process. We have compiled here the available data concerning the unique ability of norepinephrine to increase cell proliferation and inhibit apoptosis in brown adipocytes. Adrenergically stimulated cell proliferation is fully mediated via β-adrenoceptors and occurs through activation of stem cells in the tissue; intracellular mediation of the signal involves cAMP and protein kinase A activation, but activation of Erk1/2 is not part of the pathway. Apoptosis inhibition in brown adipocytes is induced by both β- and α-adrenergic receptors and here the intracellular pathway includes Erk1/2 activation. This unique ability of norepinephrine to increase cell number in an apparently mitogenically dormant tissue provides possibilities to augment the metabolic capacity of brown adipose tissue, also for therapeutic purposes.
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http://dx.doi.org/10.1016/j.bbalip.2018.06.013DOI Listing
January 2019

Optimal housing temperatures for mice to mimic the thermal environment of humans: An experimental study.

Mol Metab 2018 01 31;7:161-170. Epub 2017 Oct 31.

Department of Molecular Biosciences, The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address:

Objectives: The laboratory mouse is presently the most common model for examining mechanisms of human physiology and disease. Housing temperatures can have a large impact on the outcome of such experiments and on their translatability to the human situation. Humans usually create for themselves a thermoneutral environment without cold stress, while laboratory mice under standard conditions (≈20° C) are under constant cold stress. In a well-cited, theoretical paper by Speakman and Keijer in Molecular Metabolism, it was argued that housing mice under close to standard conditions is the optimal way of modeling the human metabolic situation. This tenet was mainly based on the observation that humans usually display average metabolic rates of about 1.6 times basal metabolic rate. The extra heat thereby produced would also be expected to lead to a shift in the 'lower critical temperature' towards lower temperatures.

Methods: To examine these tenets experimentally, we performed high time-resolution indirect calorimetry at different environmental temperatures on mice acclimated to different housing temperatures.

Results: Based on the high time-resolution calorimetry analysis, we found that mice already under thermoneutral conditions display mean diurnal energy expenditure rates 1.8 times higher than basal metabolism, remarkably closely resembling the human situation. At any temperature below thermoneutrality, mice metabolism therefore exceeds the human equivalent: Mice under standard conditions display energy expenditure 3.1 times basal metabolism. The discrepancy to previous conclusions is probably attributable to earlier limitations in establishing true mouse basal metabolic rate, due to low time resolution. We also found that the fact that mean energy expenditure exceeds resting metabolic rate does not move the apparent thermoneutral zone (the lower critical temperature) downwards.

Conclusions: We show that housing mice at thermoneutrality is an advantageous step towards aligning mouse energy metabolism to human energy metabolism.
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http://dx.doi.org/10.1016/j.molmet.2017.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784327PMC
January 2018

What Ignites UCP1?

Cell Metab 2017 11;26(5):697-698

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

We thought we knew how the heat-producing uncoupling protein 1 in brown adipose tissue was activated: by fatty acids released upon lipid droplet breakdown in the brown adipocytes. However, two studies in this issue (Schreiber et al., 2017; Shin et al., 2017) imply that this classical model may not be valid: heat can be produced in brown fat without intracellular lipolysis.
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http://dx.doi.org/10.1016/j.cmet.2017.10.012DOI Listing
November 2017

Adaptive facultative diet-induced thermogenesis in wild-type but not in UCP1-ablated mice.

Am J Physiol Endocrinol Metab 2017 11 5;313(5):E515-E527. Epub 2017 Jul 5.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden

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.
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http://dx.doi.org/10.1152/ajpendo.00097.2017DOI Listing
November 2017

Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis.

Nat Med 2017 May 17;23(5):623-630. Epub 2017 Apr 17.

Diabetes, Metabolism and Obesity Institute, Icahn School of Medicine at Mount Sinai, NY 10029, USA.

Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through β3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow-derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 (Ucp1), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1 and interleukin-4 receptor-α double-negative (Il4ra) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis.
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http://dx.doi.org/10.1038/nm.4316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420449PMC
May 2017

The β-adrenergic receptor is dispensable for browning of adipose tissues.

Am J Physiol Endocrinol Metab 2017 06 21;312(6):E508-E518. Epub 2017 Feb 21.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden

Brown and brite/beige adipocytes are attractive therapeutic targets to treat metabolic diseases. To maximally utilize their functional potential, further understanding is required about their identities and their functional differences. Recent studies with β-adrenergic receptor knockout mice reported that brite/beige adipocytes, but not classical brown adipocytes, require the β-adrenergic receptor for cold-induced transcriptional activation of thermogenic genes. We aimed to further characterize this requirement of the β-adrenergic receptor as a functional distinction between classical brown and brite/beige adipocytes. However, when comparing wild-type and β-adrenergic receptor knockout mice, we observed no differences in cold-induced thermogenic gene expression (, , , and ) in brown or white (brite/beige) adipose tissues. Irrespective of the duration of the cold exposure or the sex of the mice, we observed no effect of the absence of the β-adrenergic receptor. Experiments with the β-adrenergic receptor agonist CL-316,243 verified the functional absence of β-adrenergic signaling in these knockout mice. The β-adrenergic receptor knockout model in the present study was maintained on a FVB/N background, whereas earlier reports used C57BL/6 and 129Sv mice. Thus our data imply background-dependent differences in adrenergic signaling mechanisms in response to cold exposure. Nonetheless, the present data indicate that the β-adrenergic receptor is dispensable for cold-induced transcriptional activation in both classical brown and, as opposed to earlier studies, brite/beige cells.
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http://dx.doi.org/10.1152/ajpendo.00437.2016DOI Listing
June 2017

Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1.

Aging (Albany NY) 2017 02;9(2):315-339

The Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden.

MtDNA mutator mice exhibit marked features of premature aging. We find that these mice treated from age of ≈100 days with the mitochondria-targeted antioxidant SkQ1 showed a delayed appearance of traits of aging such as kyphosis, alopecia, lowering of body temperature, body weight loss, as well as ameliorated heart, kidney and liver pathologies. These effects of SkQ1 are suggested to be related to an alleviation of the effects of an enhanced reactive oxygen species (ROS) level in mtDNA mutator mice: the increased mitochondrial ROS released due to mitochondrial mutations probably interact with polyunsaturated fatty acids in cardiolipin, releasing malondialdehyde and 4-hydroxynonenal that form protein adducts and thus diminishes mitochondrial functions. SkQ1 counteracts this as it scavenges mitochondrial ROS. As the results, the normal mitochondrial ultrastructure is preserved in liver and heart; the phosphorylation capacity of skeletal muscle mitochondria as well as the thermogenic capacity of brown adipose tissue is also improved. The SkQ1-treated mice live significantly longer (335 versus 290 days). These data may be relevant in relation to treatment of mitochondrial diseases particularly and the process of aging in general.
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http://dx.doi.org/10.18632/aging.101174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361666PMC
February 2017

Leptin-deficient mice are not hypothermic, they are anapyrexic.

Mol Metab 2017 02 9;6(2):173. Epub 2016 Nov 9.

Department of Molecular Biosciences, The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden. Electronic address:

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http://dx.doi.org/10.1016/j.molmet.2016.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5279901PMC
February 2017

UCP1 in adipose tissues: two steps to full browning.

Biochimie 2017 Mar 18;134:127-137. Epub 2017 Jan 18.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden. Electronic address:

The possibility that brown adipose tissue thermogenesis can be recruited in order to combat the development of obesity has led to a high interest in the identification of "browning agents", i.e. agents that increase the amount and activity of UCP1 in brown and brite/beige adipose tissues. However, functional analysis of the browning process yields confusingly different results when the analysis is performed in one of two alternative steps. Thus, in one of the steps, using cold acclimation as a potent model browning agent, we find that if the browning process is followed in mice initially housed at 21 °C (the most common procedure), there is only weak molecular evidence for increases in UCP1 gene expression or UCP1 protein abundance in classical brown adipose tissue; however, in brite/beige adipose depots, there are large increases, apparently associating functional browning with events only in the brite/beige tissues. Contrastingly, in another step, if the process is followed starting with mice initially housed at 30 °C (thermoneutrality for mice, thus similar to normal human conditions), large increases in UCP1 gene expression and UCP1 protein abundance are observed in the classical brown adipose tissue depots; there is then practically no observable UCP1 gene expression in brite/beige tissues. This apparent conundrum can be resolved when it is realized that the classical brown adipose tissue at 21 °C is already essentially fully differentiated and thus expands extensively through proliferation upon further browning induction, rather than by further enhancing cellular differentiation. When the limiting factor for thermogenesis, i.e. the total amount of UCP1 protein per depot, is analyzed, classical brown adipose tissue is by far the predominant site for the browning process, irrespective of which of the two steps is analyzed. There are to date no published data demonstrating that alternative browning agents would selectively promote brite/beige tissues versus classical brown tissue to a higher degree than does cold acclimation. Thus, to restrict investigations to examine adipose tissue depots where only a limited part of the adaptation process occurs (i.e. the brite/beige tissues) and to use initial conditions different from the thermoneutrality normally experienced by adult humans may seriously hamper the identification of therapeutically valid browning agents. The data presented here have therefore important implications for the analysis of the potential of browning agents and the nature of human brown adipose tissue.
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http://dx.doi.org/10.1016/j.biochi.2017.01.007DOI Listing
March 2017

UCP1 inhibition in Cidea-overexpressing mice is physiologically counteracted by brown adipose tissue hyperrecruitment.

Am J Physiol Endocrinol Metab 2017 01 6;312(1):E72-E87. Epub 2016 Dec 6.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden;

Cidea is a gene highly expressed in thermogenesis-competent (UCP1-containing) adipose cells, both brown and brite/beige. Here, we initially demonstrate a remarkable adipose-depot specific regulation of Cidea expression. In classical brown fat, Cidea mRNA is expressed continuously and invariably, irrespective of tissue recruitment. However, Cidea protein levels are regulated posttranscriptionally, being conspicuously induced in the thermogenically recruited state. In contrast, in brite fat, Cidea protein levels are regulated at the transcriptional level, and Cidea mRNA and protein levels are proportional to tissue "briteness." Although routinely followed as a thermogenic molecular marker, Cidea function is not clarified. Here, we employed a gain-of-function approach to examine a possible role of Cidea in the regulation of thermogenesis. We utilized transgenic aP2-hCidea mice that overexpress human Cidea in all adipose tissues. We demonstrate that UCP1 activity is markedly suppressed in brown-fat mitochondria isolated from aP2-hCidea mice. However, mitochondrial UCP1 protein levels were identical in wild-type and transgenic mice. This implies a regulatory effect of Cidea on UCP1 activity, but as we demonstrate that Cidea itself is not localized to mitochondria, we propose an indirect inhibitory effect. The Cidea-induced inhibition of UCP1 activity (observed in isolated mitochondria) is physiologically relevant since the mice, through an appropriate homeostatic compensatory mechanism, increased the total amount of UCP1 in the tissue to exactly match the diminished thermogenic capacity of the UCP1 protein and retain unaltered nonshivering thermogenic capacity. Thus, we verified Cidea as being a marker of thermogenesis-competent adipose tissues, but we conclude that Cidea, unexpectedly, functions molecularly as an indirect inhibitor of thermogenesis.
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http://dx.doi.org/10.1152/ajpendo.00284.2016DOI Listing
January 2017

Reply to letter to the editor: at thermoneutrality, neither the lean nor the obese freeze.

Am J Physiol Endocrinol Metab 2016 09;311(3):E639

Department of Molecular Biosciences, The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, Stockholm, Sweden; and

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http://dx.doi.org/10.1152/ajpendo.00309.2016DOI Listing
September 2016