Role of β-adrenergic receptors in the hyperphagic and hypermetabolic responses to dietary methionine restriction

Abstract

Dietary methionine restriction (MR) limits fat deposition and decreases plasma leptin, while increasing food consumption, total energy expenditure (EE), plasma adiponectin, and expression of uncoupling protein 1 (UCP1) in brown and white adipose tissue (BAT and WAT). beta-adrenergic receptors (beta-AR) serve as conduits for sympathetic input to adipose tissue, but their role in mediating the effects of MR on energy homeostasis is unclear. Energy intake, weight, and adiposity were modestly higher in beta(3)-AR(-/-) mice on the Control diet compared with wild-type (WT) mice, but the hyperphagic response to the MR diet and the reduction in fat deposition did not differ between the genotypes. The absence of beta(3)-ARs also did not diminish the ability of MR to increase total EE and plasma adiponectin or decrease leptin mRNA, but it did block the MR-dependent increase in UCP1 mRNA in BAT but not WAT. In a further study, propranolol was used to antagonize remaining beta-adrenergic input (beta(1)- and beta(2)-ARs) in beta(3)-AR(-/-) mice, and this treatment blocked >50% of the MR-induced increase in total EE and UCP1 induction in both BAT and WAT. We conclude that signaling through beta-adrenergic receptors is a component of the mechanism used by dietary MR to increase EE, and that beta(1)- and beta(2)-ARs are able to substitute for beta(3)-ARs in mediating the effect of dietary MR on EE. These findings are consistent with the involvement of both UCP1-dependent and -independent mechanisms in the physiological responses affecting energy balance that are produced by dietary MR.

Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21

“…Dietary manipulation in the form of MR has been shown before to dramatically decrease body weight and adiposity and improve insulin sensitivity in young, healthy mice (Hasek et al ., 2010, 2013; Perrone et al ., 2010; Plaisance et al ., 2010). We have shown here for the first time that MR is able to reverse aging-associated alterations in physiology, specifically to decrease body fat, increase physical activity, and improve glucose and lipid homeostasis to the levels measured in young mice (fed a normal diet).…”

“…Methionine restriction has been shown previously to extend lifespan (Orentreich et al ., 1993; Richie et al ., 1994), dramatically decrease body weight and adiposity, and improve insulin sensitivity relative to animals on a control diet (Hasek et al ., 2010; Plaisance et al ., 2010; Ables et al ., 2012). Methionine restriction has, therefore, been proposed to mimic effects of caloric restriction (CR) (Masoro, 2005); however, in contrast to CR, animals on MR diet are fed ad libitum and actually consume more food than control-fed animals (Hasek et al ., 2010; Plaisance et al ., 2010). This loss in body mass despite an increase in energy intake is thought to be accomplished through creating a vast metabolic inefficiency, which leads to increased energy expenditure, through uncoupling protein 1 (UCP1) nonshivering thermogenesis in adipose tissue (Hasek et al ., 2010).…”

Methionine restriction improves renal insulin signalling in aged kidneys

“…Moreover, dietary MR improves insulin sensitivity and glucose/lipid homeostasis in rodents and humans (7,19,22,23).…”

Methionine restriction slows down senescence in human diploid fibroblasts

“…Of interest, lifespan extension by MetR has been associated with increased expression of mitochondrial uncoupling protein 1 (UCP1) in the brown adipose tissue of both rats (Hasek et al ., 2010) and mice (Plaisance et al ., 2010). This finding suggests that beneficial effects of MetR in rodents may be related at least in part to UCP1 expression in brown fat.…”