Age-related Metabolic Diseases Research Articles

Incorporation of Bone Morphogenetic Protein-2 and Osteoprotegerin in 3D-Printed Ti6Al4V Scaffolds Enhances Osseointegration Under Osteoporotic Conditions.

Osteoporosis is an age-related metabolic disease that results in limited bone regeneration capacity and excessive osteoclast activity. After arthroplasty in patients with osteoporosis, poor interface osseointegration resulting from insufficient bone regeneration ability often leads to catastrophic complications such as prosthesis displacement and loosening and periprosthetic fractures. In this study, we prepared a thermosensitive hydrogel loaded with bone morphogenetic protein-2 (BMP-2) to promote osteogenesis and osteoprotegerin (OPG) to inhibit excessive osteoclast activity. To construct three-dimensional (3D)-printed composite scaffolds for implantation, a hydrogel loaded with drugs was injected into porous Ti6Al4V scaffolds. The 3D-printed composite scaffolds showed good biocompatibility and sustained release of BMP-2 and OPG for more than 20 days. In vitro experiments indicated that composite scaffolds promoted osteogenic differentiation and reduced the osteoclastic activation simultaneously. Remarkably, immunofluorescence staining, micro-CT, histological, and biomechanical tests demonstrated that the sustained release of both BMP-2 and OPG from composite scaffolds significantly improved bone ingrowth and osseointegration in osteoporotic defects. In conclusion, this study demonstrated that the BMP-2- and OPG-loaded 3D-printed composite scaffolds can potentially promote osseointegration for osteoporotic patients after joint replacement.

Phenotypic and genotypic changes in obesity and type 2 diabetes of male KK mice with aging.

Research into the prevention and treatment of age-related metabolic diseases are important in the present-day situation of the aging population. We propose that an elderly diabetic mouse model may be useful to such research as it exhibits deterioration of glucose and lipid metabolism. Although the KK mouse strain is commonly used as a model of moderate obesity and type 2 diabetes, the utility of this strain as an elderly obese and diabetic model mouse for research into aging remains unclear. The present study aimed to investigate age-related changes of glucose and lipid metabolism in male KK mice fed a standard chow diet. We demonstrate that 40 weeks KK mice exhibit age-related dysfunctions, such as development of insulin resistance associated with pancreatic islet hypertrophy and decreased lipolysis in white adipose tissue (WAT) compared with 15 weeks KK mice. However, aging does not appear to cause mitochondrial dysfunction of brown adipose tissue. Unexpectedly, hyperglycemia, potential glucose uptake in insulin-sensitive organs, hepatic lipid accumulation, hypertrophy of adipocytes, and inflammation in epididymal WAT did not worsen but rather compensated in 40 weeks KK mice. Our data indicate that the use of male KK mice as an elderly obese and diabetic mouse model has some limitations and in order to represent a useful elderly obese and diabetic animal model, it may be necessary to induce deterioration of glucose and lipid metabolism in KK mice through breeding with high-sucrose or high-fat diets.

SARS-CoV-2, COVID-19 and the Ageing Immune System.

The coronavirus disease 2019 (COVID-19) pandemic is a global health threat with particular risk for severe disease and death in older adults and in adults with age-related metabolic and cardiovascular disease. Recent advances in the science of ageing have highlighted how ageing pathways control not only lifespan but also healthspan, the healthy years of life. Here, we discuss the ageing immune system and its ability to respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We specifically focus on the intersect of severe COVID-19 and immunosenescence to highlight pathways that may be determinant for the risk of complications and death following infection with SARS-CoV-2. New or adapted therapeutics that target ageing-associated pathways may be important tools to reduce the burden of death and long-term disability caused by this pandemic. Proposed interventions aimed at immunosenescence could enhance immune function not only in the elderly but in susceptible younger individuals as well, ultimately improving complications of severe COVID-19 for all ages.

Hypoxia Inducible Factor (HIF)‐1α is a Transcriptional Mediator for Thiamine Insufficiency Induced Neurotoxicity

Age-dependent decline in vitamin B1 (thiamine) levels has a devastating impact on the brain parenchyma. The neurotoxicity promoted by chronic thiamine insufficiency (TI) is a well-established comorbidity of Alzheimer's Disease (AD), the most prevalent age-related metabolic neurodegenerative disease. Inadequate levels of blood thiamine and derivates highly correlate with senile dementia prognosis as predictive peripheral AD biomarker. Impaired activity of thiamine-dependent enzymes due to TI, dramatically decreased cerebral oxidative metabolism promoting oxidative stress, mitochondrial damage, inflammation, and eventually neuronal loss. Furthermore, age-related decline in TI potentiates the AD neuropathology triggering the amyloid plaque formation and hyperphosphorylation of tau. We previously showed that TI stabilizes Hypoxia Inducible Factor -1α (HIF-1α), the main transcription factor involved in hypoxic stress, leading to HIF-1α induced pro-apoptotic and pro-inflammatory response. Among the transcriptionally activated HIF-1α target genes, TI triggered the expression of the pro-apoptotic protein BCL2/adenovirus E1B 19 kDa protein-interacting protein-3 (BNIP-3). Induction of BNIP-3 leads to its mitochondria migration where eventually triggers cell death via loss of membrane potential and increase in reactive oxygen species. To date, despite the well-established correlation between TI and neuropathogenesis, the molecular mechanism underlying the TI mediated neurotoxicity is still unknown. Therefore, we hypothesize that HIF-1α may be a critical upstream mediator between thiamine insufficiency and neurotoxicity. In this study, hippocampal murine cells (HT22) treated in TI conditions exhibited a significant increase in protein and mRNA levels of HIF-1α. Increase in BNIP-3 and other HIF-1α target genes (LDHA, VEGF, BACE-1, MCP-1) implicated in pro-inflammatory and pro-apoptotic response was also detected. Treatment with 50 μM and 100 μM of the thiamine antagonist Pyrithiamine (PT) up to 5 days significantly decrease HT22 viability to 30% and 20%, respectively. HIF-1α silencing via shRNA attenuated the neurotoxic response improving viability up to 60% with the same PT doses. In order to better characterize the HIF-1α response, BNIP-3 was also silenced via shRNA. In congruency with HIF-1α shRNA result, we found a 2-fold decrease in PT-induced toxicity in BNIP-3 shRNA transduced cells. Localization of BNIP-3 in mitochondria and loss of mitochondrial potential after PT treatment further highlighted the involvement of the HIF-1α - BNIP-3 response in TI induced neuronal death. Overall, these findings suggest a central role for HIF-1α as upstream regulator in TI mediated neurotoxicity.

Mitochondrial Functionality in Inflammatory Pathology-Modulatory Role of Physical Activity.

The incidence and severity of metabolic diseases can be reduced by introducing healthy lifestyle habits including moderate exercise. A common observation in age-related metabolic diseases is an increment in systemic inflammation (the so-called inflammaging) where mitochondrial reactive oxygen species (ROS) production may have a key role. Exercise prevents these metabolic pathologies, at least in part, due to its ability to alter immunometabolism, e.g., reducing systemic inflammation and by improving immune cell metabolism. Here, we review how exercise regulates immunometabolism within contracting muscles. In fact, we discuss how circulating and resident macrophages alter their function due to mitochondrial signaling, and we propose how these effects can be triggered within skeletal muscle in response to exercise. Finally, we also describe how exercise-induced mitochondrial adaptations can help to fight against virus infection. Moreover, the fact that moderate exercise increases circulating immune cells must be taken into account by public health agencies, as it may help prevent virus spread. This is of interest in order to face not only acute respiratory-related coronavirus (SARS-CoV) responsible for the COVID-19 pandemic but also for future virus infection challenges.

Taa Cells and Granzyme K: Old Players with New Tricks

Inflammaging is associated with chronic diseases, but tissue-specific changes in the immune system remain unknown. In this issue of Immunity, Mogilenko etal. use single-cell RNA sequencing, flow cytometry, and mass cytometry to describe age-related differences, including the accumulation of age-associated Tcells that contribute to inflammaging.

Live-Cell Imaging of Sirtuin Activity Using a One-Step Fluorescence Probe.

Sirtuins (SIRTs) are a family of NAD+-dependent histone deacetylases (HDACs). In mammals, dysfunction of SIRTs is associated with age-related metabolic diseases, cancers, and even aging. Therefore, the detection of SIRT activity in living cells or tissues would be helpful for diagnosis of a wide range of SIRT-associated diseases. Here, we present methodology to measure SIRT activity in living cells by using our newly developed SIRT fluorescence probe, KST-F-DA.

Solvent accessibility changes in a Na+-dependent C4-dicarboxylate transporter suggest differential substrate effects in a multistep mechanism

The divalent anion sodium symporter (DASS) family (SLC13) plays critical roles in metabolic homeostasis, influencing many processes, including fatty acid synthesis, insulin resistance, and adiposity. DASS transporters catalyze the Na+-driven concentrative uptake of Krebs cycle intermediates and sulfate into cells; disrupting their function can protect against age-related metabolic diseases and can extend lifespan. An inward-facing crystal structure and an outward-facing model of a bacterial DASS family member, VcINDY from Vibrio cholerae, predict an elevator-like transport mechanism involving a large rigid body movement of the substrate-binding site. How substrate binding influences the conformational state of VcINDY is currently unknown. Here, we probe the interaction between substrate binding and protein conformation by monitoring substrate-induced solvent accessibility changes of broadly distributed positions in VcINDY using a site-specific alkylation strategy. Our findings reveal that accessibility to all positions tested is modulated by the presence of substrates, with the majority becoming less accessible in the presence of saturating concentrations of both Na+ and succinate. We also observe separable effects of Na+ and succinate binding at several positions suggesting distinct effects of the two substrates. Furthermore, accessibility changes to a solely succinate-sensitive position suggests that substrate binding is a low-affinity, ordered process. Mapping these accessibility changes onto the structures of VcINDY suggests that Na+ binding drives the transporter into an as-yet-unidentified conformational state, involving rearrangement of the substrate-binding site–associated re-entrant hairpin loops. These findings provide insight into the mechanism of VcINDY, which is currently the only structurally characterized representative of the entire DASS family.

Gut microbiota transplantation from db/db mice induces diabetes-like phenotypes and alterations in Hippo signaling in pseudo germ-free mice.

Type 2 diabetes mellitus (T2DM) is an age-related metabolic disease that is of increasing concern. Gut microbiota might have a critical role in the pathogenesis of T2DM. Additionally, Hippo signaling has been associated strongly with the progression of T2DM and the aging process. We adopted db/db male mice as a T2DM model, and the gut microbiota of db/db and m/m mice were transplanted successfully into pseudo germ-free mice. Furthermore, Hippo signaling, including mammalian sterile 20-like protein kinases 1 (MST1), large tumor suppressors 1 (LATS1), Yes-associated protein (YAP), and phosphorylation of YAP (p-YAP) in peripheral tissues were significantly altered and highly correlated with blood glucose in db/db mice. Interestingly, the host after gut microbiota transplantation from db/db mice showed decreased MST1 and LATS1 levels, and p-YAP/YAP ratio in the heart, liver, and kidney compared to those from m/m mice. Negative correlations between fasting blood glucose and Hippo signaling levels in selected peripheral tissues also were identified. These findings suggest that alterations in Hippo signaling in selected peripheral tissues may contribute to the development of T2DM, and that therapeutic interventions improving Hippo signaling by gut microbiota transplantation might be beneficial for the treatment of T2DM and other age-related metabolic diseases.

Alterations of Specific Lymphocytic Subsets with Aging and Age-Related Metabolic and Cardiovascular Diseases.

To investigate the association of immunosenescence with aged-related morbidity in the elderly, a clinical study was conducted to analyze and compare the alterations in peripheral blood (PB) T-cell subsets among young healthy (YH) controls, elderly healthy (EH) controls, and age-matched elderly patients with metabolic diseases (E-MDs), with cardiovascular diseases (E-CVDs) or with both (E-MDs/E-CVDs). The frequencies of CD3T, CD8T and invariant natural killer T (iNKT) cells were decreased in the EH, E-MD and E-CVD cohorts, indicating a decline in defense function. Although CD4T and regulatory T (Treg) cell frequencies tended to increase with aging, they were lower in patients with E-MDs and E-CVDs. Subset analyses of T-cells consistently showed the accumulation of senescent T-cell in aging and in patients with E-MDs and E-CVDs, compared with YH volunteers. These accumulated senescent T-cells were undergoing apoptosis upon stimulation due to the replicative senescence stage of T-cells. In addition, serum levels of cytokines, including interferon (IF)-γ, transforming growth factor (TGF)-β and growth differentiation factor (GDF)-15, consistently reflected alterations in T-cell subsets. This study demonstrated that T-cell subset changes with paralleled alterations in cytokines were associated with aging and age-related pathogenesis. These altered T-cell subsets and/or cytokines can potentially serve as biomarkers for the prevention, diagnosis and treatment of age-related morbidities.

Epidemiology, risk factors across the spectrum of age-related metabolic diseases

BackgroundPopulation aging is dynamic process of increasing proportion of older adults in the total population, which is an inescapable result of decline in fertility rate and extension in life expectancy. Inevitably, age-related metabolic diseases, for example obesity, type 2 diabetes, metabolic syndrome, dyslipidemia, and nonalcoholic fatty liver disease, are becoming epidemic globally along with the demographic transition. ContentThe review examines the literatures related to: 1) the epidemiology of age related metabolic diseases including obesity, type 2 diabetes, metabolic syndrome, dyslipidemia, and nonalcoholic fatty liver disease; and 2) the risk factors of age related metabolic diseases including genetic factors, diet, smoking, Physical activity, intestinal microbiota and environmental factors. ConclusionPopulation aging is becoming epidemic worldwide, resulting in increasing incidence and prevalence of a serious of age-related metabolic diseases. Both genetic and environmental factors contribute to the diseases, thus interventions targeting on these factors may have beneficial effect on the development of age-related metabolic diseases.

Mitochondrial Dysfunction in Age-Related Metabolic Disorders.

Aging is a natural biological process in living organisms characterized by receding bioenergetics. Mitochondria are crucial for cellular bioenergetics and thus an important contributor to age-related energetics deterioration. In addition, mitochondria play a major role in calcium signaling, redox homeostasis, and thermogenesis making this organelle a major cellular component that dictates the fate of a cell. To maintain its quantity and quality, mitochondria undergo multiple processes such as fission, fusion, and mitophagy to eliminate or replace damaged mitochondria. While this bioenergetics machinery is properly protected, the functional decline associated with age and age-related metabolic diseases is mostly a result of failure in such protective mechanisms. In addition, metabolic by-products like reactive oxygen species also aid in this destructive pathway. Mitochondrial dysfunction has always been thought to be associated with diseases. Moreover, studies in recent years have pointed out that aging contributes to the decay of mitochondrial health by promoting imbalances in key mitochondrial-regulated pathways. Hence, it is crucial to understand the nexus of mitochondrial dysfunction in age-related diseases. This review focuses on various aspects of basic mitochondrial biology and its status in aging and age-related metabolic diseases.

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype

Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease.

Abnormal gut microbiota composition contributes to the development of type 2 diabetes mellitus in db/db mice

It is well recognized that type 2 diabetes mellitus (T2DM) is an age-related metabolic disease, emerging gradually as a major global health burden that has gained public attention. Meanwhile, increasing attention is paid to the crucial role of gut microbiota in the pathogenesis and therapeutic mechanisms of metabolic disorders, especially T2DM. In this study, we used C57 BL/KS db/db male mice as a T2DM murine model. We found that the β-diversity and relative abundances of gut bacteria were obviously altered in db/db mice, associated with a significant increase in Verrucomicrobia at six levels (phylum, class, order, etc.) and family S24-7 and a significant decrease in Bacteroidaceae at family, genus, and species levels, as well as Prevotellaceae at family and genus levels. Furthermore, fecal bacteria from db/db and m/m mice transplanted into pseudo-germ-free mice showed a significant change in the metabolic parameters, including the body weight, fasting blood glucose, fluid and food intake, and alterations in the composition of the gut microbiota. Taken together, these findings suggest that abnormalities in the composition of the gut microbiota might contribute to the development of T2DM and that potential therapeutic strategies improving gut microbiota might provide beneficial effects for individuals with T2DM and age-related glucose intolerance.

Dehydroepiandrosterone on metabolism and the cardiovascular system in the postmenopausal period.

Dehydroepiandrosterone (DHEA), mostly present as its sulfated ester (DHEA-S), is an anabolic hormone that naturally declines with age. Furthermore, it is the most abundant androgen and estrogen precursor in humans. Low plasma levels of DHEA have been strongly associated with obesity, insulin resistance, dyslipidemia, and high blood pressure, increasing the risk of cardiovascular disease. In this respect, DHEA could be regarded as a promising agent against metabolic syndrome (MetS) in postmenopausal women, since several age-related metabolic diseases are reported during aging. There are plenty of experimental evidences showing beneficial effects after DHEA therapy on carbohydrate and lipid metabolism, as well as cardiovascular health. However, its potential as a therapeutic agent appears to attract controversy, due to the lack of effects on some symptoms related to MetS. In this review, we examine the available literature regarding the impact of DHEA therapy on adiposity, glucose metabolism, and the cardiovascular system in the postmenopausal period. Both clinical studies and in vitro and in vivo experimental models were selected, and where possible, the main cellular mechanisms involved in DHEA therapy were discussed. Schematic representation showing some of the general effects observed after administration DHEA therapy on target tissues of energy metabolism and the cardiovascular system. ↑ represents an increase, ↓ represents a decrease, - represents a worsening and ↔ represents no change after DHEA therapy.

Inhibition of Mitochondrial Calcium Overload by SIRT3 Prevents Obesity- or Age-Related Whitening of Brown Adipose Tissue.

The whitening and loss of brown adipose tissue (BAT) during obesity and aging promote metabolic disorders and related diseases. The imbalance of Ca2+ homeostasis accounts for the dysfunction and clearance of mitochondria during BAT whitening. Capsaicin, a dietary factor activating TRPV1, can inhibit obesity induced by high-fat diet (HFD), but whether capsaicin inhibits BAT loss and the underlying mechanism remain unclear. In this study, we determined that the inhibitory effects of capsaicin on HFD-induced obesity and BAT whitening were dependent on the participation of SIRT3, a critical mitochondrial deacetylase. SIRT3 also mediated all of the beneficial effects of capsaicin on alleviating reactive oxygen species generation, elevating mitochondrial activity, and restricting mitochondrial calcium overload induced by HFD. Mechanistically, SIRT3 inhibits mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium overload by reducing the H3K27ac level on the MCU promoter in an AMPK-dependent manner. In addition, HFD also inhibits AMPK activity to reduce SIRT3 expression, which could be reversed by capsaicin. Capsaicin intervention also inhibited aging-induced BAT whitening through this mechanism. In conclusion, this study emphasizes a critical role of the AMPK/SIRT3 pathway in the maintenance of BAT morphology and function and suggests that intervention in this pathway may be an effective target for preventing obesity- or age-related metabolic diseases.

Brown and Beige Adipose Tissue and Aging.

Across aging, adipose tissue (AT) changes its quantity and distribution: AT becomes dysfunctional with an increase in production of inflammatory peptides, a decline of those with anti-inflammatory activity and infiltration of macrophages. Adipose organ dysfunction may lead to age-related metabolic alterations. Aging is characterized by an increase in adiposity and a decline in brown adipose tissue (BAT) depots and activity, and UCP1 expression. There are many possible links to age-associated involution of BAT, including the loss of mitochondrial function, impairment of the sympathetic nervous system, age-induced alteration of brown adipogenic stem/progenitor cell function and changes in endocrine signals. Aging is also associated with a reduction in beige adipocyte formation. Beige adipocytes are known to differentiate from a sub-population of progenitors resident in white adipose tissue (WAT); a defective ability of progenitor cells to proliferate and differentiate has been hypothesized with aging. The loss of beige adipocytes with age may be caused by changes in trophic factors in the adipose tissue microenvironment, which regulate progenitor cell proliferation and differentiation. This review focuses on possible mechanisms involved in the reduction of BAT and beige activity with aging, along with possible targets for age-related metabolic disease therapy.

Comparison of multi-tissue aging between human and mouse

With the rapid growth of the aging population, exploring the biological basis of aging and related molecular mechanisms has become an important topic in modern scientific research. Aging can cause multiple organ function attenuations, leading to the occurrence and development of various age-related metabolic, nervous system, and cardiovascular diseases. In addition, aging is closely related to the occurrence and development of tumors. Although a number of studies have used various mouse models to study aging, further research is needed to associate mouse and human aging at the molecular level. In this paper, we systematically assessed the relationship between human and mouse aging by comparing multi-tissue age-related gene expression sets. We compared 18 human and mouse tissues, and found 9 significantly correlated tissue pairs. Functional analysis also revealed some terms related to aging in human and mouse. And we performed a crosswise comparison of homologous age-related genes with 18 tissues in human and mouse respectively, and found that human Brain_Cortex was significantly correlated with Brain_Hippocampus, which was also found in mouse. In addition, we focused on comparing four brain-related tissues in human and mouse, and found a gene–GFAP–related to aging in both human and mouse.

SAT-LB024 Imprecision in Biomarker Analysis: Major Hurdle to Detection and Reversal of Disorders of Aging?

Age-related metabolic diseases, such as CVD and diabetes (prediabetes and insulin resistance), are major contributors to morbidity, mortality, and healthcare costs, which are now estimated at over $350 billion per year in direct expenditures (National Assoc. Biomedical Res, 2016). Biomarkers are essential to diagnosis and manage these common diseases. Yet, clinical indicators such as HbA1C, fasting glucose, and insulin vary widely over time when measured at various (CLIA) labs and should not be the sole drivers to diagnose, monitor, or intervene, particularly when using pharmaceuticals. 100 subjects were assessed with FG, insulin, and HbA1C through two reputable labs for each of two sets of lab tests (Draws 1 and 2). The samples were taken from the same blood draw, identical protocol, procedure and shipping. Significant differences were found (p<.05) between all 3 biomarkers at 2 points in time, separated by 4 to 6 months. When comparing deltas between the two time points, there significant differences in absolute values. Moreover, the direction of the delta was inconsistent between labs. In some subjects, the biomarkers in Lab A revealed increases in FG, insulin, and/or HbA1C, while Lab B showed decreases in the same values drawn at precisely the same time and handled identically. The differences documented between two labs were not systematic, and clinically challenging to interpret. Differences in deltas were even more dramatic when using separate labs for Draws 1 and 2. The choice of laboratory significantly impacts diagnosis and interventions, ultimately impairing accurate outcomes and limiting informed decision-making. Laboratory options are typically dictated by variables outside of the physician control, such as insurance coverage, location, and practice policies. These inter-laboratory variations must be taken into consideration when exploring therapeutic management. Lack of biomarker precision highlights the need for a deeper understanding of alternative modalities to monitor patients with disorders of aging, adaptable advances that are synergistic to biomarkers, such as wearable continuous glucose monitors, and education to lead awareness on the part of clinician with respect to choices in partnering their patients. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Methionine Restriction Diet Improves Metabolic Function in Obese C57BL/6 Female Mice via AMPK/SIRT1/PGC1α Pathway

Methionine restriction has been proven to reverse age and obesity related metabolic diseases. Basically, MR regulates energy homeostasis in the whole body contributing to enhanced insulin sensitivity and improved redox status. There is no studies until now that comprehensively focus on the impact of MR on reproduction performance. The aim of this work was to investigate the reproductive system response of female obese model toward MR and clarify the possible mechanism. Females C57BL/6 were subjected to control diet (CON, 0.86% methionine + 4% fat), High Fat Diet (HFD, 0.86% methionine + 20% fat), High fat methionine Restricted diet (MR, 0.17% methionine + 20% fat). HFD showed impaired reproduction performance characteristic by impaired conception ability and lactation difficulties. MR improved oxidative stress, metabolic parameters, mammary and ovarian morphology. MR enhanced ovulation, lactation, and especially regulated metabolism efficiency via AMPK/SIRT1/PGC1. This study is the first to suggest that MR can ameliorate reproductive disorders induced by obesity.