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

Abstract 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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Chronic cold exposure has no effect on brown adipose tissue in newborn lambs born to well-fed ewes

Reproduction Fertility and Development ◽

10.1071/rd99050 ◽

1999 ◽

Vol 11 (8) ◽

pp. 415 ◽

Cited By ~ 3

Author(s):

J. J. Gate ◽

L. Clarke ◽

M. A. Lomax ◽

M. E. Symonds

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Cold Exposure ◽

Metabolizable Energy ◽

Energy Requirements ◽

Perirenal Adipose Tissue ◽

Tissue Weight ◽

Adipose Tissue Weight ◽

Brown Adipose ◽

The Impact

It has been previously shown in twin-bearing ewes fed only 60% of their metabolizable energy requirements for late pregnancy that chronic cold exposure induced by winter shearing of the ewes results in larger lambs with more brown adipose tissue. This effect appears to be primarily due to prevention of a decline in fetal body and tissue weights between 145 days’ gestation and 2 h after birth (i.e. 147 days’ gestation) in lambs born to underfed shorn ewes. The present study therefore examined the impact, in ewes that were well fed (i.e. received 100% of their metabolizable energy requirements) during the final month of gestation, of chronic cold exposure induced by winter shearing on lamb birthweight and perirenal adipose tissue composition as measured 2 h after birth. Perirenal adipose tissue was analysed for its thermogenic activity (i.e. GDP binding to mitochondria) and catecholamine content. These observations were combined with similar measurements made in near-term (i.e. 145 days’ gestation) fetuses sampled from well-fed unshorn ewes. There was no difference between lambs born to shorn or unshorn ewes with respect to birth-weight or perirenal adipose tissue weight and composition. Perirenal adipose tissue weight was higher in lambs born to unshorn ewes than in fetuses. The thermogenic activity of adipose tissue was 2-fold higher in lambs born to unshorn ewes compared with 145-day-old fetuses. Epinephrine was detectable only at very low levels in fetal perirenal adipose tissue, increasing 10-fold after birth, with no difference between lambs born to shorn or unshorn ewes. In newborn lambs, plasma growth hormone concentration was lower and insulin concentration higher in shorn compared with unshorn groups. In conclusion, chronic cold exposure induced by winter shearing had no effect on brown adipose tissue development in lambs born to well-fed ewes.

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Brown adipose tissue is involved in the seasonal variation of cold-induced thermogenesis in humans

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00057.2015 ◽

2016 ◽

Vol 310 (10) ◽

pp. R999-R1009 ◽

Cited By ~ 32

Author(s):

Takeshi Yoneshiro ◽

Mami Matsushita ◽

Satoshi Nakae ◽

Toshimitsu Kameya ◽

Hiroki Sugie ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Cold Exposure ◽

Multivariate Regression Analysis ◽

Tympanic Temperature ◽

Whole Body ◽

Dependent Manner ◽

Significant Interaction Effect ◽

Brown Adipose ◽

The Impact

Brown adipose tissue (BAT) contributes to whole body energy expenditure (EE), especially cold-induced thermogenesis (CIT), in humans. Although it is known that EE and CIT vary seasonally, their relationship with BAT has not been investigated. In the present study, we examined the impact of BAT on seasonal variations of EE/CIT and thermal responses to cold exposure in a randomized crossover design. Forty-five healthy male volunteers participated, and their BAT was assessed by positron emission tomography and computed tomography. CIT, the difference of EE at 27°C and after 2-h cold exposure at 19°C, significantly increased in winter compared with summer, being greater in subjects with metabolically active BAT (High BAT, 185.6 kcal/day vs. 18.3 kcal/day, P < 0.001) than those without (Low BAT, 90.6 kcal/day vs. −46.5 kcal/day, P < 0.05). Multivariate regression analysis revealed a significant interaction effect between season and BAT on CIT ( P < 0.001). The cold-induced drop of tympanic temperature (Tty) and skin temperature (Tskin) in the forehead region and in the supraclavicular region close to BAT deposits were smaller in the High BAT Group than in the Low BAT Group in winter but not in summer. In contrast, the drop of Tskin in the subclavicular and peripheral regions distant from BAT was similar in the two groups in both seasons. In conclusion, CIT increased from summer to winter in a BAT-dependent manner, paralleling cold-induced changes in Tty/Tskin, indicating a role of BAT in seasonal changes in the thermogenic and thermal responses to cold exposure in humans.

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Gene Expression Analysis of Environmental Temperature and High-Fat Diet-Induced Changes in Mouse Supraclavicular Brown Adipose Tissue

Cells ◽

10.3390/cells10061370 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1370

Author(s):

Yufeng Shi ◽

Honglei Zhai ◽

Sharon John ◽

Yi-Ting Shen ◽

Yali Ran ◽

...

Keyword(s):

Gene Expression ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Cold Exposure ◽

High Fat Diet ◽

High Fat ◽

Nutrient Processing ◽

Expression Of Genes ◽

Brown Adipose ◽

Attractive Therapeutic Target

Obesity, a dysregulation of adipose tissue, is a major health risk factor associated with many diseases. Brown adipose tissue (BAT)-mediated thermogenesis can potentially regulate energy expenditure, making it an attractive therapeutic target to combat obesity. Here, we characterize the effects of cold exposure, thermoneutrality, and high-fat diet (HFD) feeding on mouse supraclavicular BAT (scBAT) morphology and BAT-associated gene expression compared to other adipose depots, including the interscapular BAT (iBAT). scBAT was as sensitive to cold induced thermogenesis as iBAT and showed reduced thermogenic effect under thermoneutrality. While both scBAT and iBAT are sensitive to cold, the expression of genes involved in nutrient processing is different. The scBAT also showed less depot weight gain and more single-lipid adipocytes, while the expression of BAT thermogenic genes, such as Ucp1, remained similar or increased more under our HFD feeding regime at ambient and thermoneutral temperatures than iBAT. Together, these findings show that, in addition to its anatomical resemblance to human scBAT, mouse scBAT possesses thermogenic features distinct from those of other adipose depots. Lastly, this study also characterizes a previously unknown mouse deep neck BAT (dnBAT) depot that exhibits similar thermogenic characteristics as scBAT under cold exposure and thermoneutrality.

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Circadian lipid synthesis in brown fat maintains murine body temperature during chronic cold

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1909883116 ◽

2019 ◽

Vol 116 (37) ◽

pp. 18691-18699 ◽

Cited By ~ 2

Author(s):

Marine Adlanmerini ◽

Bryce J. Carpenter ◽

Jarrett R. Remsberg ◽

Yann Aubert ◽

Lindsey C. Peed ◽

...

Keyword(s):

Lipid Metabolism ◽

Body Temperature ◽

Cold Exposure ◽

De Novo ◽

Lipid Synthesis ◽

Acid Synthesis ◽

High Amplitude ◽

De Novo Lipogenesis ◽

Brown Adipose ◽

The Impact

Ambient temperature influences the molecular clock and lipid metabolism, but the impact of chronic cold exposure on circadian lipid metabolism in thermogenic brown adipose tissue (BAT) has not been studied. Here we show that during chronic cold exposure (1 wk at 4 °C), genes controlling de novo lipogenesis (DNL) includingSrebp1, the master transcriptional regulator of DNL, acquired high-amplitude circadian rhythms in thermogenic BAT. These conditions activated mechanistic target of rapamycin 1 (mTORC1), an inducer ofSrebp1expression, and engaged circadian transcriptional repressors REV-ERBα and β as rhythmic regulators ofSrebp1in BAT. SREBP was required in BAT for the thermogenic response to norepinephrine, and depletion of SREBP prevented maintenance of body temperature both during circadian cycles as well as during fasting of chronically cold mice. By contrast, deletion of REV-ERBα and β in BAT allowed mice to maintain their body temperature in chronic cold. Thus, the environmental challenge of prolonged noncircadian exposure to cold temperature induces circadian induction of SREBP1 that drives fuel synthesis in BAT and is necessary to maintain circadian body temperature during chronic cold exposure. The requirement for BAT fatty acid synthesis has broad implications for adaptation to cold.

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Increased expression of glucose transporter GLUT-4 in brown adipose tissue of fasted rats after cold exposure

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.6.e890 ◽

1993 ◽

Vol 264 (6) ◽

pp. E890-E895 ◽

Cited By ~ 14

Author(s):

Y. Shimizu ◽

H. Nikami ◽

K. Tsukazaki ◽

U. F. Machado ◽

H. Yano ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Glucose Uptake ◽

Cold Exposure ◽

De Novo ◽

Mrna Levels ◽

Glut 4 ◽

Increase Glucose Uptake ◽

Brown Adipose ◽

Stimulation Of

Cold exposure has been shown to increase glucose uptake specifically in brown adipose tissue (BAT), the major site for sympathetically controlled metabolic heat production. In this study, the relationship between glucose uptake and glucose transporters (GLUT) was examined in rats exposed to cold for various periods. To minimize the stimulatory effect of circulating insulin, all animals were starved for 20-24 h before the measurements. Acute (4 h) cold exposure had no effect on protein and mRNA levels of GLUT-4, the predominant isoform of GLUT in BAT, despite a significant increase in cellular glucose uptake. Prolonged (1-10 days) cold exposure produced a parallel increase in GLUT-4 expression and glucose uptake in BAT. In contrast, cold exposure had no noticeable effect on GLUT-1, another isoform of GLUT in BAT, and on GLUT-4 in other insulin-sensitive tissues such as white adipose tissue and muscles. The increased glucose uptake and GLUT-4 expression were completely abolished after surgical sympathetic denervation. These findings suggest that cold exposure increases glucose uptake in BAT by at least two distinct mechanisms, both of which are dependent on sympathetic nerve: 1) an increase in the amount of GLUT-4 due to the stimulation of its de novo synthesis, and 2) an increase without stimulation of GLUT synthesis, probably due to the change in the transport activity of GLUT-4 and/or its translocation from an intracellular pool to the plasma membrane.

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