Metabolomic profile of diet-induced obesity mice in response to humanin and small humanin-like peptide 2 treatment

Abstract

Introduction The mitochondrial-derived peptides (MDPs) are a novel group of natural occurring peptides that have important signaling functions and biological activity. Both humanin and small-humanin-like peptide 2 (SHLP2) have been reported to act as insulin sensitizers and modulate metabolism. Objectives By using a metabolomic approach, this study explores how the plasma metabolite profile is regulated in response to humanin and SHLP2 treatment in a diet-induced obesity (DIO) mouse model. The results also shed light on the potential mechanism underlying MDPs’ insulin sensitization effects. Methods Plasma samples were obtained from DIO mice subjected to vehicle (water) treatment, or peptide treatment with either humanin analog S14G (HNG) or SHLP2 (n = 6 per group). Vehicle or peptides were given as intraperitoneal (IP) injections twice a day at dose of 2.5 mg/kg/injection for 3 days. Metabolites in plasma samples were comprehensively identified and quantified using UPLC-MS/MS. Results HNG and SHLP2 administration significantly altered the concentrations of amino acid and lipid metabolites in plasma. Among all the metabolic pathways, the glutathione and sphingolipid metabolism responded most strongly to the peptide treatment. Conclusions The present study indicates that humanin and SHLP2 can lower several markers associated with age-related metabolic disorders. With the previous understanding of the effects of humanin and SHLP2 on cardiovascular function, insulin sensitization, and anti-inflammation, this metabolomic discovery provides a more comprehensive molecular explanation of the mechanism of action for humanin and SHLP2 treatment. Electronic supplementary material The online version of this article (10.1007/s11306-019-1549-7) contains supplementary material, which is available to authorized users.

The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan

“…In this study, midlife humanin treatment attenuated the obesity that occurs in mid-life, but did not exacerbate the gradual decline in bodyweight at older ages. This improvement in metabolic parameters has been previously seen in mice treated with HNG and in fact, human studies have found that HN levels were negatively correlated with HbA1c levels and triglyceride levels [29,44]. Taken together, even at the low doses that we administered to middleaged mice, humanin treatment improved several lifespan and healthspan markers such as metabolism, fibrosis, and cognitive decline [41,68].…”

“…Perhaps because of the compact nature of the mitochondria and absence of introns, MDPs are encoded in alternative open reading frames within known genes. These MDPs are a novel group of micropeptides encoded within the mitochondrial genome and have been shown to have a large number of biological effects [27][28][29][30][31][32].…”

The mitochondrial‐derived peptide MOTS‐c is a regulator of plasma metabolites and enhances insulin sensitivity

“…Currently, eight MDPs have been proposed to be biologically active and to be protective or detrimental factors of certain conditions. We recently published the effect of other MDPs: humanin and SHLP2 on plasma metabolites in DIO mice (Mehta et al, ). Humanin and SHLP2 commonly regulate several metabolic pathways: glutathione, sphingolipid, gamma‐glutamyl cycle, and carnitine metabolism.…”

“…Humanin and SHLP2 commonly regulate several metabolic pathways: glutathione, sphingolipid, gamma‐glutamyl cycle, and carnitine metabolism. Humanin and SHLP2 exert common biological functions (Mehta et al, ). Both peptides activate AKT, ERK, and STAT3 signaling pathways, and exhibit insulin sensitization as well as anti‐apoptosis effects (Cobb et al, ; Kim et al, ).…”

High-protein and low-calorie diets improved the anti-aging Klotho protein in the rats’ brain: the toxic role of high-fat diet

“…Aging is the consequence of some developments; during physiological aging, some changes happened in the body, such as decreased food and energy intake. Diet is one of the extrinsic factors, which could control our body's metabolism [1]. Focus on dietary protocol and supplements are necessary for older people.…”