Abstract
Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS‐R), attenuates age‐associated obesity and insulin resistance. Ghrelin and obestatin are derived from the same preproghrelin gene. Here we showed that in brown adipocytes, ghrelin decreases the expression of thermogenic regulator but obestatin increases it, thus showing the opposite effects. We also found that during aging, plasma ghrelin and GHS‐R expression in brown adipose tissue (BAT) are increased, but plasma obestatin is unchanged. Increased plasma ghrelin and unchanged obestatin during aging may lead to an imbalance of thermogenic regulation, which may in turn exacerbate thermogenic impairment in aging. Moreover, we found that GHS‐R ablation activates thermogenic signaling, enhances insulin activation, increases mitochondrial biogenesis, and improves mitochondrial dynamics of BAT. In addition, we detected increased norepinephrine in the circulation, and observed that GHS‐R knockdown in brown adipocytes directly stimulates thermogenic activity, suggesting that GHS‐R regulates thermogenesis via both central and peripheral mechanisms.Collectively, our studies demonstrate that ghrelin signaling is an important thermogenic regulator in aging. Antagonists of GHS‐R may serve as unique anti‐obesity agents, combating obesity by activating thermogenesis.
Highlights
Obesity and diabetes have reached epidemic proportions in all age groups, but are most pronounced among the elderly [1, 2]
We previously showed that ghrelin decreases UCP1 expression in brown adipocyte HIB1B cells through Growth Hormone Secretagogue Receptor (GHS-R) [34]
Current data suggest that obestatin increases UCP1 expression in HIB1B cells, while des-acyl ghrelin (DAG) has no effect
Summary
Obesity and diabetes have reached epidemic proportions in all age groups, but are most pronounced among the elderly [1, 2]. Nonshivering thermogenesis in BAT was recently recognized to play a crucial role in energy balance in rodents and human neonates [3, 5,6,7]. Thermogenic activity of BAT is positively correlated with energy expenditure, and dysregulation of thermogenesis in BAT is linked to obesity in humans [6]. Studies have shown that enhanced thermogenesis improves glucose homeostasis and insulin sensitivity in animals [8] and humans [9]. These results suggest that interventions to increase BAT mass and/or activity may be very attractive strategies for prevention/treatment of obesity and diabetes
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