The suppression of ghrelin signaling mitigates age-associated thermogenic impairment

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.

Ghrelin receptor controls obesity by fat burning

“…Dysfunctions of mitochondrial energetics is linked to dysfunction of aging neuronal and muscular systems [7], but the roles of mitochondria in thermogenic regulation during aging are not clear. Our recent studies recently published in Aging have revealed that GHS-R ablation activates thermogenic signaling in BAT by enhancing mitochondrial biogenesis, and improving both mitochondrial fission and fusion in brown fat (Figure 1) [8]. In addition, we have detected increased norepinephrine in the circulation and higher β3-AR expression in BAT of old Ghsr -null mice; and that GHS-R knockdown in brown adipocytes directly stimulates thermogenic activity.…”

Obesity and related consequences to ageing

“…Animal studies showed relatively stable Ucp1 mRNA levels in adult mice (Xue et al 2005;Chabowska-Kita et al 2015); nonetheless, BAT activity was shown to diminish in ageing (Seale and Lazar 2009). It has been suggested that ageing may be associated with impaired thermogenesis as suggested by greater reduction of BAT activity in old men compared to young ones (Seale and Lazar 2009;McDonald and Horwitz 1999;Lin et al 2014). Additionally, age-dependent loss of thermogenic capacity is associated with a decline in UCP1 activity but not in UCP1 protein (Valle et al 2008).…”

“…Cumulative molecular damage leads to mitochondrial impairment (Detmer and Chan 2007), and its functional decline is linked to an age-dependent increase in the pathogenesis of metabolic disorders and neurodegenerative diseases (Lin et al 2014;Detmer and Chan 2007). On the other hand, it has been shown that lifelong dietary caloric restriction, which decelerates ageing, can attenuate the age-related decline in mitochondrial mass and uncoupling protein levels in BAT of rats (Valle et al 2008).…”

“…On the other hand, it has been shown that lifelong dietary caloric restriction, which decelerates ageing, can attenuate the age-related decline in mitochondrial mass and uncoupling protein levels in BAT of rats (Valle et al 2008). Although it has been proposed that changes in circulating levels of thyroid and sex hormones might contribute to the age-related decline in BAT activity (Mattson 2010), the main components underlying the dysfunction of BAT in ageing are still unknown (Lin et al 2014).…”

Deletion of G-protein-coupled receptor 55 promotes obesity by reducing physical activity

“…Each mouse received an intraperitoneal injection of glucose solution (Sigma-Aldrich) at a dose of 2 g/kg body weight. Blood was collected from the tail at 0, 15, 30, and 120 minutes after glucose injection, as previously described 18 . The blood glucose concentration was measured using the commercially available OneTouch Ultra glucometer and test strips (LifeScan), and insulin was measured using Sensitive Rat Insulin RIA kit (SRI-13K) from EMD Millipore, following the manufacturer's instructions.…”