Aging leads to a programmed loss of brown adipocytes in murine subcutaneous white adipose tissue

Abstract

SUMMARY 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 sub-population of energy dissipating UCP1+ brown adipocytes, promote age-dependent progression towards 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 ®3- adrenergic agonist to compensate for reduced tone rescues the aged sWAT phenotype. Age- related changes in sWAT are not explained by differences in body weight; mice subjected to 40% caloric restriction for 12 months are of similar body weight 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 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.

Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity

“…Because Ucp1 expression was increased modestly in the brown fat pads of Tg-4EBP1mt-muscle mice (Supplemental Figure 8, B and C), we investigated the fate of brown fat in more detail. Loss of "browning" in brown adipose tissue has been correlated with increasing age (56,57). At 17 months of age, we found marked white adipocyte infiltration in the brown fat pads of control mice.…”

Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing

“…1f inset) 14 . In agreement, aging upregulates MAOA protein (Extended Data 2e) 15 . Collectively, these data suggested a link between reduced adipocyte lipolysis and elevated catecholamine catabolism machinery in ATMs during aging.…”

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“…We and others have shown that GHS-R is highly expressed in hypothalamus, but its expression in peripheral tissues is very low in young mice. Intriguingly, circulating ghrelin and GHS-R expression in the brain and adipose tissues increase during aging [4,5]. We have reported in Aging Cell that old Ghsr-null mice are lean and insulin-sensitive, exhibiting a healthier metabolic profile similar to that of young animals [6].…”

“…Beside the classical brown adipocytes present in BAT, brown-adipocyte-like "beige" cells residing in WAT also have thermogenic properties [3]. Aging is associated with programmed loss of "beige" cells [4]. Animal studies reveal that thermogenic activation in brown and beige adipocytes protects against obesity.…”