Regulates insulin sensitivity and metabolic homeostasis (PubMed:25738459, PubMed:33468709). Inhibits the folate cycle, thereby reducing de novo purine biosynthesis which leads to the accumulation of the de novo purine synthesis intermediate 5-aminoimidazole-4-carboxamide (AICAR) and the activation of the metabolic regulator 5'-AMP-activated protein kinase (AMPK) (PubMed:25738459). Protects against age-dependent and diet-induced insulin resistance as well as diet-induced obesity (PubMed:25738459). In response to metabolic stress, translocates to the nucleus where it binds to antioxidant response elements (ARE) present in the promoter regions of a number of genes and plays a role in regulating nuclear gene expression in an NFE2L2-dependent manner and increasing cellular resistance to metabolic stress (PubMed:29983246). Increases mitochondrial respiration and levels of CPT1A and cytokines IL1B, IL6, IL8, IL10 and TNF in senescent cells (PubMed:29886458). Increases activity of the serine/threonine protein kinase complex mTORC2 and reduces activity of the PTEN phosphatase, thus promoting phosphorylation of AKT (PubMed:33554779). This promotes AKT-mediated phosphorylation of transcription factor FOXO1 which reduces FOXO1 activity, leading to reduced levels of MSTN and promotion of skeletal muscle growth (PubMed:33554779). Promotes osteogenic differentiation of bone marrow mesenchymal stem cells via the TGFB/SMAD pathway (PubMed:30468456). Promotes osteoblast proliferation and osteoblast synthesis of type I collagens COL1A1 and COL1A2 via the TGFB/SMAD pathway (PubMed:31081069). Interacts with transcription factors ATF1 and NFE2L2/NRF2; the interactions occur in the nucleus following metabolic stress (PubMed:29983246). Also interacts with transcription factor NFE2L1/NRF1 (PubMed:29983246). Translocates to the nucleus in response to metabolic stress in an AMPK-dependent manner. Detected in plasma (at protein level) (PubMed:25738459, PubMed:32182209). Also expressed in skeletal muscle (at protein level) (PubMed:32182209). Circulating plasma levels decrease with age while levels in skeletal muscle increase with age (at protein level). By exercise (PubMed:33473109). Up-regulated during cellular senescence (PubMed:29886458). Increases survival and decreases bacterial load in mice infected with methicillin-resistant Staphylococcus aureus (MRSA) (PubMed:29096170). Reduces serum levels of inflammatory cytokines such as TNF and IL6 and increases levels of the anti-inflammatory cytokine IL10 (PubMed:29096170). Enhances the phagocytic and bactericidal ability of macrophages and suppresses MAPK pathways while enhancing activation of STAT3 and AHR (PubMed:29096170). Protects mice against lipopolysaccharide-induced acute lung injury (PubMed:31931370). Reduces body weight loss and pulmonary edema, inhibits neutrophilic tissue infiltration in lung tissue, reduces inflammatory cytokine levels, increases levels of anti-inflammatory cytokines and superoxide dismutase and down-regulates the expression of chemokine CXCL1/CINC1 and adhesion molecule ICAM1 in lung tissues (PubMed:31931370). Promotes cold adaptation in mice following acute cold exposure (PubMed:31109005). Prevents acute cold-induced liver lipid deposition and increases brown fat activation and white fat browning upon acute cold exposure (PubMed:31109005). Also increases expression of thermogenic genes in vitro (PubMed:31109005). In a mouse osteolysis model, rescues bone loss, protects bone mass and alleviates inflammation (PubMed:31369811). Decreases TNFSF11/RANKL expression, increases TNFRSF11B/OPG expression and reduces the number of pro-inflammatory macrophages (PubMed:31369811). In ovarietomized mice, prevents body weight gain, reduces fat mass and adipocyte size, enhances brown fat function, decreases plasma lipid and hepatic triacylglycerol levels, and prevents insulin resistance. Reduces weight gain in male mice fed a high-fat diet and enhances glucose clearance (PubMed:33468709). Does not reduce weight gain in females on a high-fat diet (PubMed:33468709). Improves physical performance in both young and aging mice and enhances skeletal muscle adaptation to metabolic stress in vitro. Reduces vascular calcification (VC) in a rat VC model (PubMed:31694019). Reverses VC-induced reduction in AMPK phosphorylation and decreases expression of receptors AGTR1 and EDNRB (PubMed:31694019). This peptide has been shown to be biologically active but is the product of a mitochondrial gene. Usage of the mitochondrial genetic code yields tandem start and stop codons so translation must occur in the cytoplasm. The mechanisms allowing the production and secretion of the peptide remain unclear.