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Klein Hazebroek, Marlou
Publications (4 of 4) Show all publications
Klein Hazebroek, M., Laterveer, R., Kutschke, M., Ramsak Marceta, V., Barthem, C. S. & Keipert, S. (2023). Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21. Scientific Reports, 13(1), Article ID 10288.
Open this publication in new window or tab >>Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21
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2023 (English)In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, no 1, article id 10288Article in journal (Refereed) Published
Abstract [en]

Increasing energy expenditure through uncoupling protein 1 (UCP1) activity in thermogenic adipose tissue is widely investigated to correct diet-induced obesity (DIO). Paradoxically, UCP1-deficient male mice are resistant to DIO at room temperature. Recently, we uncovered a key role for fibroblast growth factor 21 (FGF21), a promising drug target for treatment of metabolic disease, in this phenomenon. As the metabolic action of FGF21 is so far understudied in females, we aim to investigate potential sexual dimorphisms. Here, we confirm that male UCP1 KO mice display resistance to DIO in mild cold, without significant changes in metabolic parameters. Surprisingly, females gained the same amount of body fat as WT controls. Molecular regulation was similar between UCP1 KO males and females, with an upregulation of serum FGF21, coinciding with beiging of inguinal white adipose tissue and induced lipid metabolism. While energy expenditure did not display significant differences, UCP1 KO females significantly increased their food intake. Altogether, our results indicate that hyperphagia is likely counteracting the beneficial effects of FGF21 in female mice. This underlines the importance of sex-specific studies in (pre)clinical research for personalized drug development.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-221146 (URN)10.1038/s41598-023-37264-0 (DOI)001018464000031 ()37355753 (PubMedID)2-s2.0-85162810710 (Scopus ID)
Available from: 2023-09-15 Created: 2023-09-15 Last updated: 2023-09-15Bibliographically approved
Cavalieri, R., Klein Hazebroek, M., Cotrim, C. A., Lee, Y., Kunji, E. R. S., Jastroch, M., . . . Crichton, P. G. (2022). Activating ligands of Uncoupling protein 1 identified by rapid membrane protein thermostability shift analysis. Molecular Metabolism, 62, Article ID 101526.
Open this publication in new window or tab >>Activating ligands of Uncoupling protein 1 identified by rapid membrane protein thermostability shift analysis
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2022 (English)In: Molecular Metabolism, ISSN 2212-8778, Vol. 62, article id 101526Article in journal (Refereed) Published
Abstract [en]

Objective: Uncoupling protein 1 (UCP1) catalyses mitochondrial proton leak in brown adipose tissue to facilitate nutrient oxidation for heat production, and may combat metabolic disease if activated in humans. During the adrenergic stimulation of brown adipocytes, free fatty acids generated from lipolysis activate UCP1 via an unclear interaction. Here, we set out to characterise activator binding to purified UCP1 to clarify the activation process, discern novel activators and the potential to target UCP1.

Methods: We assessed ligand binding to purified UCP1 by protein thermostability shift analysis, which unlike many conventional approaches can inform on the binding of hydrophobic ligands to membrane proteins. A detailed activator interaction analysis and screening approach was carried out, supported by investigations of UCP1 activity in liposomes, isolated brown fat mitochondria and UCP1 expression-controlled cell lines.

Results: We reveal that fatty acids and other activators influence UCP1 through a specific destabilising interaction, behaving as transport substrates that shift the protein to a less stable conformation of a transport cycle. Through the detection of specific stability shifts in screens, we identify novel activators, including the over-the-counter drug ibuprofen, where ligand analysis indicates that UCP1 has a relatively wide structural specificity for interacting molecules. Ibuprofen successfully induced UCP1 activity in liposomes, isolated brown fat mitochondria and UCP1-expressing HEK293 cells but not in cultured brown adipocytes, suggesting drug delivery differs in each cell type.

Conclusions: These findings clarify the nature of the activator-UCP1 interaction and demonstrate that the targeting of UCP1 in cells by approved drugs is in principle achievable as a therapeutic avenue, but requires variants with more effective delivery in brown adipocytes.

Keywords
Ligand binding, Thermal stability assay, Differential scanning fluorimetry, Brown adipose tissue, Proton transport, Energy expenditure, Mitochondrial carrier
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:su:diva-210301 (URN)10.1016/j.molmet.2022.101526 (DOI)000861054600004 ()35691529 (PubMedID)2-s2.0-85132531588 (Scopus ID)
Available from: 2022-10-11 Created: 2022-10-11 Last updated: 2022-10-11Bibliographically approved
Klein Hazebroek, M. & Keipert, S. (2022). Obesity-resistance of UCP1-deficient mice associates with sustained FGF21 sensitivity in inguinal adipose tissue. Frontiers in Endocrinology, 13, Article ID 909621.
Open this publication in new window or tab >>Obesity-resistance of UCP1-deficient mice associates with sustained FGF21 sensitivity in inguinal adipose tissue
2022 (English)In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 13, article id 909621Article in journal (Refereed) Published
Abstract [en]

Metabolic diseases represent the major health burden of our modern society. With the need of novel therapeutic approaches, fibroblast growth factor 21 (FGF21) is a promising target, based on metabolic improvements upon FGF21 administration in mice and humans. Endogenous FGF21 serum levels, however, are increased during obesity-related diseases, suggesting the development of FGF21 resistance during obesity and thereby lowering FGF21 efficacy. In uncoupling protein 1 knockout (UCP1 KO) mice, however, elevated endogenous FGF21 levels mediate resistance against diet-induced obesity. Here, we show that after long-term high fat diet feeding (HFD), circulating FGF21 levels become similarly high in obese wildtype and obesity-resistant UCP1 KO mice, suggesting improved FGF21 sensitivity in UCP1 KO mice. To test this hypothesis, we injected FGF21 after long-term HFD and assessed the metabolic and molecular effects. The UCP1 KO mice lost weight directly upon FGF21 administration, whereas body weights of WT mice resisted weight loss in the initial phase of the treatment. The FGF21 treatment induced expression of liver Pck1, a typical FGF21-responsive gene, in both genotypes. In iWAT, FGF21-responsive genes were selectively induced in UCP1 KO mice, strongly associating FGF21-sensitivity in iWAT with healthy body weights. Thus, these data support the concept that FGF21-sensitivity in adipose tissue is key for metabolic improvements during obesogenic diets.

Keywords
FGF21 resistance, beige fat, diet induced obesity, beta klotho, browning, FGF21 sensitivity
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:su:diva-209432 (URN)10.3389/fendo.2022.909621 (DOI)000844074800001 ()36034414 (PubMedID)2-s2.0-85136541127 (Scopus ID)
Available from: 2022-09-20 Created: 2022-09-20 Last updated: 2024-01-17Bibliographically approved
Klein Hazebroek, M. & Keipert, S. (2020). Adapting to the Cold: A Role for Endogenous Fibroblast Growth Factor 21 in Thermoregulation?. Frontiers in Endocrinology, 11, Article ID 389.
Open this publication in new window or tab >>Adapting to the Cold: A Role for Endogenous Fibroblast Growth Factor 21 in Thermoregulation?
2020 (English)In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 11, article id 389Article, review/survey (Refereed) Published
Abstract [en]

Fibroblast growth factor 21 (FGF21) is in biomedical focus as a treatment option for metabolic diseases, given that administration improves metabolism in mice and humans. The metabolic effects of exogenous FGF21 administration are well-characterized, but the physiological role of endogenous FGF21 has not been fully understood yet. Despite cold-induced FGF21 expression and increased circulating levels in some studies, which co-occur with brown fat thermogenesis, recent studies in cold-acclimated mice demonstrate the dispensability of FGF21 for maintenance of body temperature, thereby questioning FGF21's role for thermogenesis. Here we discuss the evidence either supporting or opposing the role of endogenous FGF21 for thermogenesis based on the current literature. FGF21, secreted by brown fat or liver, is likely not required for energy homeostasis in the cold, but the nutritional conditions could modulate the interaction between FGF21, energy metabolism, and thermoregulation.

Keywords
cold exposure, brown adipose tissue, beige adipose tissue, uncoupling protein 1, endocrine signaling, low protein diet, energy metabolism
National Category
Endocrinology and Diabetes Biological Sciences
Identifiers
urn:nbn:se:su:diva-184528 (URN)10.3389/fendo.2020.00389 (DOI)000553271800001 ()32714278 (PubMedID)
Available from: 2020-09-09 Created: 2020-09-09 Last updated: 2024-01-17Bibliographically approved
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