Sex Differences in Brown Adipose Tissue Function: Sex Hormones, Glucocorticoids, and Their Crosstalk

Kaikaew, Kasiphak; Grefhorst, Aldo; Visser, Jenny A.

doi:10.3389/fendo.2021.652444

Cited by 52 publications

(48 citation statements)

References 180 publications

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“…DIO2 catalyzes the conversion of T4 to its active form, T3, which stimulates fatty acid oxidation and mitochondrial respiration in BAT [41]. Sex differences in energy expenditure can be explained by the inducing effect of estrogens on BAT activity and thermogenesis [42]. The increased expression of Ppara, Fgf21, and Pgc1 in the liver, along with an increased level of adiponectin in the blood, indicates the more intensive oxidation of fats in the liver in females than in males, since PPARa [43], PGC1 [44], FGF21, and adiponectin activate fatty acid oxidation in the liver [45].…”

Section: Discussionmentioning

confidence: 99%

The Same Metabolic Response to FGF21 Administration in Male and Female Obese Mice Is Accompanied by Sex-Specific Changes in Adipose Tissue Gene Expression

Макарова

Kazantseva

Dubinina

et al. 2021

IJMS

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The preference for high-calorie foods depends on sex and contributes to obesity development. Fibroblast growth factor 21 (FGF21) beneficially affects taste preferences and obesity, but its action has mainly been studied in males. The aim of this study was to compare the effects of FGF21 on food preferences and glucose and lipid metabolism in C57Bl/6J male and female mice with diet-induced obesity. Mice were injected with FGF21 or vehicle for 7 days. Body weight, choice between standard (SD) and high-fat (HFD) diets, blood parameters, and gene expression in white (WAT) and brown (BAT) adipose tissues, liver, muscles, and the hypothalamus were assessed. Compared to males, females had a greater preference for HFD; less WAT; lower levels of cholesterol, glucose, and insulin; and higher expression of Fgf21, Insr, Ppara, Pgc1, Acca and Accb in the liver and Dio2 in BAT. FGF21 administration decreased adiposity; blood levels of cholesterol, glucose, and insulin; hypothalamic Agrp expression, increased SD intake, decreased HFD intake independently of sex, and increased WAT expression of Pparg, Lpl and Lipe only in females. Thus, FGF21 administration beneficially affected mice of both sexes despite obesity-associated sex differences in metabolic characteristics, and it induced female-specific activation of gene expression in WAT.

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Section: Discussionmentioning

confidence: 99%

The Same Metabolic Response to FGF21 Administration in Male and Female Obese Mice Is Accompanied by Sex-Specific Changes in Adipose Tissue Gene Expression

Макарова

Kazantseva

Dubinina

et al. 2021

IJMS

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“…Fetal sex was not determined in the current study. Given the presence of sexual dimorphism in BAT mass and function in adult rodents and humans [ 39 ], fetal sex will need to be considered in future studies into fetal BAT development.…”

Section: Discussionmentioning

confidence: 99%

Maternal cold exposure induces distinct transcriptome changes in the placenta and fetal brown adipose tissue in mice

et al. 2021

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Background Brown adipose tissue (BAT) is specialized to dissipate energy in the form of heat. BAT-mediated heat production in rodents and humans is critical for effective temperature adaptation of newborns to the extrauterine environment immediately after birth. However, very little is known about whether and how fetal BAT development is modulated in-utero in response to changes in maternal thermal environment during pregnancy. Using BL6 mice, we evaluated the impact of different maternal environmental temperatures (28 °C and 18 °C) on the transcriptome of the placenta and fetal BAT to test if maternal cold exposure influences fetal BAT development via placental remodeling. Results Maternal weight gain during pregnancy, the average number of fetuses per pregnancy, and placental weight did not differ between the groups at 28 °C and 18 °C. However, the average fetal weight at E18.5 was 6% lower in the 18 °C-group compared to the 28 °C-group. In fetal BATs, cold exposure during pregnancy induced increased expression of genes involved in de novo lipogenesis and lipid metabolism while decreasing the expression of genes associated with muscle cell differentiation, thus suggesting that maternal cold exposure may promote fetal brown adipogenesis by suppressing the myogenic lineage in bidirectional progenitors. In placental tissues, maternal cold exposure was associated with upregulation of genes involved in complement activation and downregulation of genes related to muscle contraction and actin-myosin filament sliding. These changes may coordinate placental adaptation to maternal cold exposure, potentially by protecting against cold stress-induced inflammatory damage and modulating the vascular and extravascular contractile system in the placenta. Conclusions These findings provide evidence that environmental cold temperature sensed by the mother can modulate the transcriptome of placental and fetal BAT tissues. The ramifications of the observed gene expression changes warrant future investigation.

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“…Compared to Ldb1 ΔBAT male mice, which had significant reductions in EE at all temperatures, female Ldb1 ΔBAT mice only displayed reduced EE at 22 °C. Additionally, a cold challenge revealed that male Ldb1 ΔBAT mice displayed the greatest reduction in core body temperature at 4 h. Sex differences in thermogenesis may be attributed to variations in basal uncoupling capacity, sympathetic activity, fat mass composition, and hormone signaling [ 41 , 44 ]. This difference also extends to metabolic parameters, like glucose and lipid homeostasis [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

The transcriptional co-regulator LDB1 is required for brown adipose function

Kepple

Liu

Kim

et al. 2021

Molecular Metabolism

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Objective Brown adipose tissue (BAT) is critical for thermogenesis and glucose/lipid homeostasis. Exploiting the energy uncoupling capacity of BAT may reveal targets for obesity therapies. This exploitation requires a greater understanding of the transcriptional mechanisms underlying BAT function. One potential regulator of BAT is the transcriptional co-regulator LIM domain-binding protein 1 (LDB1), which acts as a dimerized scaffold, allowing for the assembly of transcriptional complexes. Utilizing a global LDB1 heterozygous mouse model, we recently reported that LDB1 might have novel roles in regulating BAT function. However, direct evidence for the LDB1 regulation of BAT thermogenesis and substrate utilization has not been elucidated. We hypothesize that brown adipocyte-expressed LDB1 is required for BAT function. Methods LDB1-deficient primary cells and brown adipocyte cell lines were assessed via qRT-PCR and western blotting for altered mRNA and protein levels to define the brown adipose-specific roles. We conducted chromatin immunoprecipitation with primary BAT tissue and immortalized cell lines. Potential transcriptional partners of LDB1 were revealed by conducting LIM factor surveys via qRT-PCR in mouse and human brown adipocytes. We developed a Ucp1 -Cre-driven LDB1-deficiency mouse model, termed Ldb1 ΔBAT , to test LDB1 function in vivo . Glucose tolerance and uptake were assessed at thermoneutrality via intraperitoneal glucose challenge and glucose tracer studies. Insulin tolerance was measured at thermoneutrality and after stimulation with cold or the administration of the β3-adrenergic receptor (β3-AR) agonist CL316,243. Additionally, we analyzed plasma insulin via ELISA and insulin signaling via western blotting. Lipid metabolism was evaluated via BAT weight, histology, lipid droplet morphometry, and the examination of lipid-associated mRNA. Finally, energy expenditure and cold tolerance were evaluated via indirect calorimetry and cold challenges. Results Reducing Ldb1 in vitro and in vivo resulted in altered BAT-selective mRNA, including Ucp1 , Elovl3 , and Dio2 . In addition, there was reduced Ucp1 induction in vitro . Impacts on gene expression may be due, in part, to LDB1 occupying Ucp1 upstream regulatory domains. We also identified BAT-expressed LIM-domain factors Lmo2 , Lmo4 , and Lhx8 , which may partner with LDB1 to mediate activity in brown adipocytes. Additionally, we observed LDB1 enrichment in human brown adipose. In vivo analysis revealed LDB1 i...

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Sex Differences in Brown Adipose Tissue Function: Sex Hormones, Glucocorticoids, and Their Crosstalk

Cited by 52 publications

References 180 publications

The Same Metabolic Response to FGF21 Administration in Male and Female Obese Mice Is Accompanied by Sex-Specific Changes in Adipose Tissue Gene Expression

The Same Metabolic Response to FGF21 Administration in Male and Female Obese Mice Is Accompanied by Sex-Specific Changes in Adipose Tissue Gene Expression

Maternal cold exposure induces distinct transcriptome changes in the placenta and fetal brown adipose tissue in mice

The transcriptional co-regulator LDB1 is required for brown adipose function

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