Meteorin-like Is a Hormone that Regulates Immune-Adipose Interactions to Increase Beige Fat Thermogenesis

Abstract

Summary Exercise training benefits many organ systems and offers protection against metabolic disorders such as obesity and diabetes. Using the recently identified isoform of PGC1-α (PGC1-α4) as a discovery tool, we report the identification of meteorin-like (Metrnl), a circulating factor that is induced in muscle after exercise and in adipose tissue upon cold exposure. Increasing circulating levels of Metrnl stimulates energy expenditure, improves glucose tolerance and the expression of genes associated with beige fat thermogenesis and anti-inflammatory cytokines. Metrnl stimulates an eosinophil-dependent increase in IL-4 expression and promotes alternative activation of adipose tissue macrophages, which are required for the increased expression of the thermogenic and anti-inflammatory gene programs in fat. Importantly, blocking Metrnl actions in-vivo significantly attenuates chronic cold exposure-induced alternative macrophage activation and thermogenic gene responses. Thus, Metrnl links host adaptive responses to the regulation of energy homeostasis and tissue inflammation, and has therapeutic potential for metabolic and inflammatory diseases.

Exercise regulation of adipose tissue

“…58 Increasing circulating Metrnl by 5-6-fold in mice by injection of adenoviral vectors increased whole-body energy expenditure, an effect associated with an increase in beiging of scWAT. 40 In addition, administration of an anti-Metrnl antibody partially prevented cold-induced beiging of scWAT, suggesting that Metrnl could be an important hormone mediating the beiging phenotype. A single bout of downhill running of mice, a form of exercise that has a large component of eccentric contractions that causes significant muscle damage, increased Metrnl mRNA expression by 3-fold in triceps, but not quadriceps muscles, 6 hours post-exercise.…”

“…39 In future studies, it will be interesting to determine if lactate plays a fundamental role in the beiging of WAT. In addition, to lactate several other putative myokines that have been implicated in beiging include irisin, 27 meteorin-like 1, 40 myostatin, 41 and b-aminoisobutyric acid. 42 It has also been proposed that exercise training results in secretion of hypothalamic brain-derived neurotrophic factor (BDNF) that signals the beiging phenotype.…”

“…These data suggest a unique role for myostatin as a muscle myokine that inhibits the beiging of scWAT. 51,57 Meteorin-like (Metrnl) Metrnl was identified from primary myotubes overexpressing PGC1a4 40 , the PGC1a splice isoform that had been shown to regulates muscle hypertrophy and energy expenditure. 58 Increasing circulating Metrnl by 5-6-fold in mice by injection of adenoviral vectors increased whole-body energy expenditure, an effect associated with an increase in beiging of scWAT.…”

The hitchhiker’s guide to PGC-1α isoform structure and biological functions

“…Several recent reports demonstrate that elevating specific PGC-1α isoforms in skeletal muscle can impact other tissues by secreting circulating factors (myokines). Irisin and β-aminoisobutyric acid (BAIBA) [52,53], both under the control of PGC-1α1, or PGC-1α4-regulated myostatin and meteorin-like protein [54,55], all convey skeletal muscle signals to adipose tissue. Thus, skeletal muscle overexpression of either PGC-1α1 or PGC-1α4 results in browning of adipose tissue, although this is achieved through distinct pathways and mechanisms specific to each isoform.…”

“…However, other research shows that both promoters can be activated independent of the exercise intervention [60,61]. PGC-1α isoform expression patterns display distinct temporal dynamics [55] and until we understand the mechanisms behind these different expression profiles it is important to unify experimental procedures such as exercise intervention, sampling and gene expression analysis techniques. One common outcome of the exercise training studies with human volunteers is that concurrent training programmes, with both endurance and resistance components, have a synergistic effect on the expression of all PGC-1α isoforms, although the effect is more pronounced on the alternative promoter.…”