Aging leads to a programmed loss of brown adipocytes in murine subcutaneous white adipose tissue
Nicole H. Rogers
Department of Metabolism and Aging, Scripps Research Institute Florida, Jupiter, FL, 33458 USA
Search for more papers by this authorAlejandro Landa
Department of Metabolism and Aging, Scripps Research Institute Florida, Jupiter, FL, 33458 USA
Search for more papers by this authorSeongjoon Park
Department of Metabolism and Aging, Scripps Research Institute Florida, Jupiter, FL, 33458 USA
Search for more papers by this authorCorresponding Author
Roy G. Smith
Department of Metabolism and Aging, Scripps Research Institute Florida, Jupiter, FL, 33458 USA
Correspondence
Roy G Smith, PhD, 130 Scripps Way #3B3, Jupiter, FL 33458, USA. Tel.: +1 561 228 2950; fax: +1 561 228 3059; e-mail: [email protected]
Search for more papers by this authorNicole H. Rogers
Department of Metabolism and Aging, Scripps Research Institute Florida, Jupiter, FL, 33458 USA
Search for more papers by this authorAlejandro Landa
Department of Metabolism and Aging, Scripps Research Institute Florida, Jupiter, FL, 33458 USA
Search for more papers by this authorSeongjoon Park
Department of Metabolism and Aging, Scripps Research Institute Florida, Jupiter, FL, 33458 USA
Search for more papers by this authorCorresponding Author
Roy G. Smith
Department of Metabolism and Aging, Scripps Research Institute Florida, Jupiter, FL, 33458 USA
Correspondence
Roy G Smith, PhD, 130 Scripps Way #3B3, Jupiter, FL 33458, USA. Tel.: +1 561 228 2950; fax: +1 561 228 3059; e-mail: [email protected]
Search for more papers by this authorSummary
Insulin sensitivity deteriorates with age, but mechanisms remain unclear. Age-related changes in the function of subcutaneous white adipose tissue (sWAT) are less characterized than those in visceral WAT. We hypothesized that metabolic alterations in sWAT, which in contrast to epididymal WAT, harbors a subpopulation of energy-dissipating UCP1+ brown adipocytes, promote age-dependent progression toward insulin resistance. Indeed, we show that a predominant consequence of aging in murine sWAT is loss of ‘browning’. sWAT from young mice is histologically similar to brown adipose tissue (multilocular, UCP1+), but becomes morphologically white by 12 months of age. Correspondingly, sWAT expression of ucp1 precipitously declines (~300-fold) between 3 and 12 months. Loss continues into old age (24 months) and is inversely correlated with the development of insulin resistance. Additional age-dependent changes in sWAT include lower expression of adbr3 and higher expression of maoa, suggesting reduced local adrenergic tone as a potential mechanism. Indeed, treatment with a β3-adrenergic agonist to compensate for reduced tone rescues the aged sWAT phenotype. Age-related changes in sWAT are not explained by the differences in body weight; mice subjected to 40% caloric restriction for 12 months are of body weight similar to 3-month-old ad lib fed mice, but display sWAT resembling that of age-matched ad lib fed mice (devoid of brown adipose-like morphology). Overall, findings identify the loss of ‘browning’ in sWAT as a new aging phenomenon and provide insight into the pathogenesis of age-associated metabolic disease by revealing novel molecular changes tied to systemic metabolic dysfunction.
Supporting Information
| Filename | Description |
|---|---|
| acel12010-sup-0001-DataS1.docxWord document, 128.3 KB | Data S1 Experimental procedures. |
| acel12010-sup-0002-TableS1-FigS1-S7.pdfapplication/PDF, 4.1 MB | Table S1 Adipogenesis PCR-array results. Fig. S1 Ucp1 and cidea expression (relative to the endogenous control 36B4) in interscapular brown adipose tissue (BAT) or subcutaneous white adipose tissue (sWAT) isolated from 5 week old male mice. N = 3. Fig. S2 Ucp1 and cidea expression (relative to endogenous control gene 36B4) in interscapular brown adipose tissue isolated from young (5 week) or old (11 month) male mice. N = 6–7. Fig. S3 QPCR-confirmation of PCR array results for ppara, pparg2, and sfrp5 expression in subcutaneous white adipose tissue isolated from young (6 weeks) and old (1 year) male mice (relative to the endogenous control tbp; n = 3–4). Fig. S4 (A) Plasma concentrations of adrenaline (white bars) and noradrenaline (black bars) are similar in young (11 weeks, gray bars) and old (11–12 months), black bars) mice. N = 4–6. (B–C) Plasma concentrations of triiodothyronine (B) and thyroxine (C) are elevated in old (12 months) vs. young (6 weeks) mice. N = 3–11; *P < 0.05, **P < 0.01. Fig. S5 Volcano plot illustrating adipogenic gene expression in subcutaneous white adipose tissue (sWAT) in mice calorically restricted (CR) vs. age-matched (AM) ad libitum fed mice. Fold changes (CR vs. AM) are plotted on the x-axis, with genes altered >2-fold either to the left (decreased) or right (increased) of the gray vertical lines, and P-values are indicated on the y-axis, with significantly altered genes above the horizontal line indicating P = 0.05. Fig. S6 Representative hematoxylin and eosin staining of epididymal white adipose tissue from mice calorically restricted for 1 year, with arrows pointing to multilocular cells. Fig. S7 Brown-adipocyte related gene expression (relative to the endogenous control 36B4) in epididymal white adipose tissue isolated from 12–13 month old mice treated with vehicle (white bars) or β-3-adrenoreceptor agonist CL 316,243 (CL, black bars) for 7 days. *P < 0.05, ***P < 0.001 vs. veh.; n = 2–5. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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