Impact of UCP1 and β3AR gene polymorphisms on age-related changes in brown adipose tissue and adiposity in humans

Abstract Age-related adipose tissue dysfunction is potentially important in the development of insulin resistance and metabolic disorder. Caloric restriction (CR) is a robust intervention to reduce adiposity, improve metabolic health, and extend healthy life span. Both white adipose tissue (WAT) and brown adipose tissue (BAT) are involved in energy homeostasis. CR triggers the beiging of WAT in young mice; however, the effects of CR on beiging of WAT and function of BAT during aging are unclear. This study aimed to investigate how age and CR impact the beiging of WAT, the function of BAT, and metabolic health in mice. C57BL/6 mice were fed CR diet (40% less than the ad libitum [AL] diet) for 3 months initiated in young (3 months), middle-aged (12 months), and old (19 months) stage. We found age-related changes in different types of adipose tissue, including adipocyte enlargement, declined beiging of WAT, and declined thermogenic and β-oxidational function of BAT. Moreover, CR attenuated age-associated adipocyte enlargement and prevented the age-related decline in beiging potential of WAT. These protective effects on the beiging potential were significant in inguinal WAT at all three ages, which were significant in epididymal WAT at young and old age. In contrast, thermogenic and β-oxidational function of BAT further declined after CR in the young age group. In conclusion, our findings reveal the contribution of WAT beiging decline to age-related metabolic disorder and suggest nutritional intervention, specifically targeting WAT beiging, as an effective approach to metabolic health during aging.

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Orexin Restores Aging-Related Brown Adipose Tissue Dysfunction in Male Mice

Endocrinology ◽

10.1210/en.2013-1629 ◽

2014 ◽

Vol 155 (2) ◽

pp. 485-501 ◽

Cited By ~ 55

Author(s):

Dyan Sellayah ◽

Devanjan Sikder

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Fat Mass ◽

Core Body Temperature ◽

Brown Adipocyte ◽

Aged Mice ◽

Age Related ◽

Brown Adipose ◽

The Impact

The aging process causes an increase in percent body fat, but the mechanism remains unclear. In the present study we examined the impact of aging on brown adipose tissue (BAT) thermogenic activity as potential cause for the increase in adiposity. We show that aging is associated with interscapular BAT morphologic abnormalities and thermogenic dysfunction. In vitro experiments revealed that brown adipocyte differentiation is defective in aged mice. Interscapular brown tissue in aged mice is progressively populated by adipocytes bearing white morphologic characteristics. Aged mice fail to mobilize intracellular fuel reserves from brown adipocytes and exhibit deficiency in homeothermy. Our results suggest a role for orexin (OX) signaling in the regulation of thermogenesis during aging. Brown fat dysfunction and age-related assimilation of fat mass were accelerated in mice in which OX-producing neurons were ablated. Conversely, OX injections in old mice increased multilocular morphology, increased core body temperature, improved cold tolerance, and reduced adiposity. These results argue that BAT can be targeted for interventions to reverse age-associated increase in fat mass.

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Age-Related Decrease in Cold-Activated Brown Adipose Tissue and Accumulation of Body Fat in Healthy Humans

Obesity ◽

10.1038/oby.2011.125 ◽

2011 ◽

Vol 19 (9) ◽

pp. 1755-1760 ◽

Cited By ~ 270

Author(s):

Takeshi Yoneshiro ◽

Sayuri Aita ◽

Mami Matsushita ◽

Yuko Okamatsu-Ogura ◽

Toshimitsu Kameya ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Body Fat ◽

Healthy Humans ◽

Age Related ◽

Brown Adipose

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Loss of FSTL1-expressing adipocyte progenitors drives the age-related involution of brown adipose tissue

10.1101/2020.05.14.096990 ◽

2020 ◽

Author(s):

Zan Huang ◽

Zengdi Zhang ◽

Ryan Heck ◽

Ping Hu ◽

Hezkiel Nanda ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Stromal Vascular Fraction ◽

Brown Adipocyte ◽

List Type ◽

Cellular Mechanisms ◽

Age Related ◽

Brown Adipose ◽

Adipocyte Progenitors ◽

Genetic Deletion

SUMMARYIn humans, brown adipose tissue (BAT) undergoes progressive involution or atrophy with increasing age, as manifested by decreased prevalence and mass, transformation to white adipose tissue (WAT), and reduction in thermogenic activity. This involution process cannot be fully recapitulated in rodent models and thus underlying cellular mechanisms are poorly understood. Here, we show that the interscapular BAT (iBAT) in rabbits involutes rapidly in early life, similarly to that in humans. The transcriptomic remodeling and identity switch of mature adipocytes are accompanied with the loss of brown adipogenic competence of their precursor cells. Through single-cell RNA sequencing, we surveyed the heterogenous populations of mesenchymal cells within the stromal vascular fraction of rabbit and human iBAT. An analogous FSTL1high population of brown adipocyte progenitors exists in both species while gradually disappear during iBAT involution in rabbits. In mice, FSTL1 is highly expressed by adipocyte progenitors in iBAT and genetic deletion of FSTL1 causes defective WNT signaling and iBAT atrophy in neonates. Our results underscore the BAT-intrinsic contribution from FSTL1high progenitors to age-related tissue involution and point to a potential therapeutic approach for obesity and its comorbidities.HIGHLIGHTSRabbit BAT irreversibly transforms to WAT before puberty.iBAT adipocyte progenitors reprogram transcriptome and lose brown adipogenic ability.Comparable FSTL1high brown adipocyte progenitors exist in rabbit and human iBAT.Loss of FSTL1 in brown adipocyte progenitors causes iBAT atrophy in mice.

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Uncoupling protein and its mRNA in brown adipose tissue of newborn rabbits

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y89-009 ◽

1989 ◽

Vol 67 (1) ◽

pp. 54-58 ◽

Cited By ~ 4

Author(s):

D. K. Rozon ◽

W. H. Harris ◽

A. M. Verrinder Gibbins

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Messenger Rna ◽

Uncoupling Protein ◽

Mitochondrial Protein ◽

Brown Fat ◽

Guanosine Diphosphate ◽

Mitochondrial Inner Membrane ◽

Age Related ◽

Brown Adipose

Guanosine diphosphate binding to the uncoupling protein of isolated mitochondria of brown adipose tissue in newborn rabbits was measured as an index of thermogenic activity. The binding was 0.281 ± 0.022 nmol GDP/mg mitochondrial protein at 1 day of age, 0.214 ± 0.017 at 3 days, 0.428 ± 0.038 at 5 days, and 0.208 ± 0.016 at 7 days. The increase in binding between 3 and 7 days of age suggests that the brown fat has an increased thermogenic capacity at that age. In addition, the potential for synthesis of the uncoupling protein was investigated in 1- to 5-day-old newborn rabbits by probing the total cellular ribonucleic acid for the messenger that codes for uncoupling protein. The amount of uncoupling protein messenger was highest at 1 day of age and declined at least until 5 days of age. Because the amount of uncoupling protein messenger decreased as the GDP binding increased, the results suggest that either the initially translated uncoupling protein was unmasked at about 5 days of age or there was a delay in the incorporation of uncoupling protein into the mitochondrial inner membrane, or both.Key words: brown fat, neonatal rabbit, thermogenin, messenger RNA, age-related changes.

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Inhibition of Mitochondrial Calcium Overload by SIRT3 Prevents Obesity- or Age-Related Whitening of Brown Adipose Tissue

Diabetes ◽

10.2337/db19-0526 ◽

2019 ◽

Vol 69 (2) ◽

pp. 165-180 ◽

Cited By ~ 6

Author(s):

Peng Gao ◽

Yanli Jiang ◽

Hao Wu ◽

Fang Sun ◽

Yaohong Li ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Calcium Overload ◽

Mitochondrial Calcium ◽

Age Related ◽

Brown Adipose

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Cold-Induced Thermoregulation and Biological Aging

Physiological Reviews ◽

10.1152/physrev.1998.78.2.339 ◽

1998 ◽

Vol 78 (2) ◽

pp. 339-358 ◽

Cited By ~ 77

Author(s):

MARIA FLOREZ-DUQUET ◽

ROGER B. McDONALD

Keyword(s):

Skeletal Muscle ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

Heat Production ◽

Biological Aging ◽

Metabolic Heat ◽

Age Related ◽

Brown Adipose ◽

Shivering Thermogenesis ◽

Thermogenic Capacity

Florez-Duquet, Maria, and Roger B. McDonald. Cold-Induced Thermoregulation and Biological Aging. Physiol. Rev. 78: 339–358, 1998. — Aging is associated with diminished cold-induced thermoregulation (CIT). The mechanisms accounting for this phenomenon have yet to be clearly elucidated but most likely reflect a combination of increased heat loss and decreased metabolic heat production. The inability of the aged subject to reduce heat loss during cold exposure is associated with diminished reactive tone of the cutaneous vasculature and, to a lesser degree, alterations in the insulative properties of body fat. Cold-induced metabolic heat production via skeletal muscle shivering thermogenesis and brown adipose tissue nonshivering thermogenesis appears to decline with age. Few investigations have directly linked diminished skeletal muscle shivering thermogenesis with the age-related reduction in cold-induced thermoregulatory capacity. Rather, age-related declines in skeletal muscle mass and metabolic activity are cited as evidence for decreased heat production via shivering. Reduced mass, GDP binding to brown fat mitochondria, and uncoupling protein (UCP) levels are cited as evidence for attenuated brown adipose tissue cold-induced nonshivering thermogenic capacity during aging. The age-related reduction in brown fat nonshivering thermogenic capacity most likely reflects altered cellular signal transduction rather than changes in neural and hormonal signaling. The discussion in this review focuses on how alterations in CIT during the life span may offer insight into possible mechanisms of biological aging. Although the preponderance of evidence presented here demonstrates that CIT declines with chronological time, the mechanism reflecting this attenuated function remains to be elucidated. The inability to draw definitive conclusions regarding biological aging and CIT reflects the lack of a clear definition of aging. It is unlikely that the mechanisms accounting for the decline in cold-induced thermoregulation during aging will be determined until biological aging is more precisely defined.

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