Higher serum resistin levels and increased frailty risk in older adults: Implications beyond metabolic function

Kwak M.K., Baek J.Y., Park S.J., Jung H., Lee E., Jang I., Ji E., Hong E., Jo Y., Ryu D., Kim B.

Abstract Context Experimental evidence indicates that resistin, an adipokine, negatively impacts muscle metabolism by hindering myogenesis. Objective To explore resistin's potential as a biomarker of muscle health in humans by examining the relationship between circulating resistin levels and sarcopenia in older adults. Design and Setting A case-control study conducted in a geriatric clinical unit. Participants The study included 247 individuals aged 65 and older who underwent comprehensive geriatric evaluations. Main Outcome Measures Sarcopenia was defined based on Asian-specific thresholds, with serum resistin concentrations measured using an enzyme-linked immunosorbent assay. Results After adjusting for sex, age, fat mass, smoking, osteoarthritis, and diabetes, participants with sarcopenia, low muscle mass, and weak muscle strength exhibited at least 27.0% higher circulating resistin concentrations than controls (P = 0.002 to 0.003). Elevated serum resistin levels were inversely associated with skeletal muscle mass, gait speed, and the short physical performance battery score, and positively associated with the time to complete five chair stands (P = 0.019 to 0.048). Higher serum resistin levels were linked to an increased risk of sarcopenia, low muscle mass, and weak muscle strength (all P = 0.005). Finally, participants in the highest resistin quartile had at least three times higher odds of having adverse muscle outcomes compared to those in the lowest quartile (P = 0.007 to 0.029). Conclusion This study is to establish a link between blood resistin levels and sarcopenia, suggesting that circulating resistin may serve as a potential biomarker reflecting poor muscle health in humans.

Deb A., Deshmukh B., Ramteke P., Bhati F.K., Bhat M.K.

• Resistin levels have been associated with several pathological disorders such as metabolic disorders, cancers etc. • Resistin exists in three isoforms namely RELM-α, β and γ. • High resistin level activates inflammatory pathways, promotes metabolic disorders and is associated with carcinogenesis. • Increase in the resistin level impairs the therapeutic response by inducing stemness or resistance, in cancer cells. • Conventional drugs which alter resistin level could have therapeutic implications in several pathological disorders. Resistin, a small secretory molecule, has been implicated to play an important role in the development of insulin resistance under obese condition. For the past few decades, it has been linked to various cellular and metabolic functions. It has been associated with diseases like metabolic disorders, cardiovascular diseases and cancers. Numerous clinical studies have indicated an increased serum resistin level in pathological disorders which have been reported to increase mortality rate in comparison to low resistin expressing subjects. Various molecular studies suggest resistin plays a pivotal role in proliferation, metastasis, angiogenesis, inflammation as well as in regulating metabolism in cancer cells. Therefore, understanding the role of resistin and elucidating its’ associated molecular mechanism will give a better insight into the management of these disorders. In this article, we summarize the diverse roles of resistin in pathological disorders based on the available literature, clinicopathological data, and a compiled study from various databases. The article mainly provides comprehensive information of its role as a target in different treatment modalities in pre as well as post-clinical studies.

Taouis M., Benomar Y.

Resistin has been firstly discovered in mice and was identified as an adipose tissue-secreted hormone or adipokine linking obesity and insulin resistance. In humans, resistin has been characterized as a hormone expressed and secreted by Immune cells especially by macrophages, and was linked to many inflammatory responses including inflammation of adipose tissue due to macrophages' infiltration. Human and mouse resistin display sequence and structural similarities and also dissimilarities that could explain their different expression pattern. In mice, strong pieces of evidence clearly associated high resistin plasma levels to obesity and insulin resistance suggesting that resistin could play an important role in the onset and progression of obesity and insulin resistance via resistin-induced inflammation. In humans, the link between resistin and obesity/insulin resistance is still a matter of debate and needs more epidemiological studies. Also, resistin has been linked to other chronic diseases such as cardiovascular diseases and cancers where resistin has been proposed in many studies as a biological marker.

Askin L., Abus S., Tanriverdi O.

: Serum resistin, mainly secreted by the bone marrow, monocytes, and macrophages, contributes to many processes, including endothelial dysfunction, Vascular Smooth Muscle Cell (VSMC) proliferation, and atherothrombosis demonstrating effects on the development of hypertension and Coronary Artery Disease (CAD). Previously published clinical studies have shown that plasma resistin levels are significantly associated with cardiovascular disease risk factors and adverse clinical outcomes associated with the condition. Resistin is associated with vascular smooth muscle cell dysfunction in vitro, most plausibly due to its relationship with oxidative stress in advanced atherosclerosis whereas in vivo studies have shown resistin to be associated with intimal hyperplasia. We aimed to summarize the role of resistin on cardiovascular disease (CVD), as we could not find any review focused on the role of resistin on CVD.

Lee H., Lee E., Jang I.

Tariq S., Tariq S., Khaliq S., Lone K.P.

Resistin, a novel adipokine may play an important role in bone metabolism. The study is designed to discover the association of bone mineral density (BMD) with serum resistin levels, anthropometric...

Kirk B., Feehan J., Lombardi G., Duque G.

Skeletal muscle and bone are connected anatomically and physiologically, and play a crucial role in human locomotion and metabolism. Historically, the coupling between muscle and bone has been viewed in light of mechanotransduction, which dictates that the mechanical forces applied to muscle are transmitted to the skeleton to initiate bone formation. However, these organs also communicate through the endocrine system, orchestrated by a family of cytokines namely myokines (derived from myocytes) and osteokines (derived from bone cells). A third player in this biochemical crosstalk is adipose tissue and the secretion of adipokines (derived from adipocytes). In this review, we discuss the bidirectional effects of myokines and osteokines on muscle and bone metabolism, and the impact of adipokines on both of these secretory organs. Several myokines, notably, IL6, irisin, IGF-1, BDNF, myostatin, and FGF2 exert anabolic/catabolic effects on bone, while the osteokines osteocalcin and sclerostin have shown to induce muscle anabolism and catabolism, respectively. Adipokines, such as leptin, resistin, adiponectin, and TNFα (released from adipose tissue), can also modulate muscle and bone metabolism. Contrarily, exercise-mediated release of lipolytic myokines (IL6, irisin, and LIF) stimulates thermogenesis by promoting the browning of adipocytes. Myokines, osteokines, and adipokines exert autocrine/paracrine effects locally as well as through the endocrine system, to regulate muscle, bone, and fat metabolism. Reductions in physical activity and increases in energy intake, both linked with aging, leads to adipocyte hypertrophy and the recruitment of immunological cells (macrophages). In turn, this releases pro-inflammatory adipokines which induces chronic low-grade inflammation (LGI), a key player in the pathology of several diseases. However, exercise-induced stimulation of bioactive cytokines, through muscle-bone-fat crosstalk, increases muscle anabolism, bone formation, mitochondrial biogenesis, glucose utilization, and fatty acid oxidation, and attenuates chronic LGI.

Tripathi D., Kant S., Pandey S., Ehtesham N.Z.

Resistin is a small secretory protein that has a pleiotropic role in rodents and humans. Both rodent resistin and human resistin have an extremely stable and high-order multimeric structure. Moreover, there is significant variation in the source of secretion and the diversity of functions of resistin. Mouse resistin resists insulin action and contributes to type 2 diabetes mellitus, while human resistin plays a role in inflammation and also functions as a small accessory chaperone. Currently, active research in the area identified a significant role for resistin in stress biology and as a biomarker in diagnostics to evaluate disease status and treatment outcome. This review summarizes recent developments within resistin biology including their association with obesity, inflammation, stress response mechanisms, and its role in clinical diagnostics.

Oh J., Song S., Rhee H., Lee S.H., Kim D.Y., Choe J.C., Ahn J., Park J.S., Shin M.J., Jeon Y.K., Lee H.W., Choi J.H., Lee H.C., Cha K.S.

Kim D.H., Afilalo J., Shi S.M., Popma J.J., Khabbaz K.R., Laham R.J., Grodstein F., Guibone K., Lux E., Lipsitz L.A.

Functional status is a patient-centered outcome that is important for a meaningful gain in health-related quality of life after aortic valve replacement.To determine functional status trajectories in the year after transcatheter aortic valve replacement (TAVR) and surgical aortic valve replacement (SAVR).A prospective cohort study with a 12-month follow-up was conducted at a single academic center in 246 patients undergoing TAVR or SAVR for severe aortic stenosis. The study was conducted between February 1, 2014, and June 30, 2017; data analysis was performed from December 27, 2017, to May 7, 2018.Preoperative comprehensive geriatric assessment was performed and a deficit-accumulation frailty index (CGA-FI) (range, 0-1; higher values indicate greater frailty) was calculated.Telephone interviews were conducted to assess self-reported ability to perform 22 activities and physical tasks at 1, 3, 6, 9, and 12 months after the procedure.Of the 246 patients included in the study, 143 underwent TAVR (74 [51.7%] women; mean [SD] age, 84.2 [5.9] years), and 103 underwent SAVR (46 [44.7%] women; age, 78.1 [5.3] years). Five trajectories were identified based on functional status at baseline and during the follow-up: from excellent at baseline to improvement at follow-up (excellent baseline-improvement), good (high baseline-full recovery), fair (moderate baseline-minimal decline), poor (low baseline-moderate decline), and very poor (low baseline-large decline). After TAVR, the most common trajectory was fair (54 [37.8%]), followed by good (33 [23.1%]), poor (21 [14.7%]), excellent (20 [14.0%]), and very poor (12 [8.4%]) trajectories. After SAVR, the most common trajectory was good (39 [37.9%]), followed by excellent (38 [36.9%]), fair (20 [19.4%]), poor (3 [2.9%]), and very poor (1 [1.0%]) trajectories. Preoperative frailty level was associated with lower probability of functional improvement and greater probability of functional decline. After TAVR, patients with CGA-FI level of 0.20 or lower had excellent (3 [50.0%]) or good (3 [50.0%]) trajectories, whereas most patients with CGA-FI level of 0.51 or higher had poor (10 [45.5%]) or very poor (5 [22.7%]) trajectories. After SAVR, most patients with CGA-FI level of 0.20 or lower had excellent (24 [58.5%]) or good (15 [36.6%]) trajectories compared with a fair trajectory (5 [71.4%]) in those with CGA-FI levels of 0.41 to 0.50. Postoperative delirium and major complications were associated with functional decline after TAVR (delirium present vs absent: 14 [50.0%] vs 11 [13.4%]; complications present vs absent: 14 [51.9%] vs 19 [16.4%]) or lack of improvement after SAVR (delirium present vs absent: 27 [69.2%] vs 31 [81.6%]; complications present vs absent: 10 [62.5%] vs 69 [79.3%]).The findings suggest that functional decline or lack of improvement is common in older adults with severe frailty undergoing TAVR or SAVR. Although this nonrandomized study does not allow comparison of the effectiveness between TAVR and SAVR, anticipated functional trajectories may inform patient-centered decision making and perioperative care to optimize functional outcomes.

O’Leary M.F., Wallace G.R., Davis E.T., Murphy D.P., Nicholson T., Bennett A.J., Tsintzas K., Jones S.W.

Adiposity and adipokines are implicated in the loss of skeletal muscle mass with age and in several chronic disease states. The aim of this study was to determine the effects of human obese and lean subcutaneous adipose tissue secretome on myogenesis and metabolism in skeletal muscle cells derived from both young (18–30 yr) and elderly (>65 yr) individuals. Obese subcutaneous adipose tissue secretome impaired the myogenesis of old myoblasts but not young myoblasts. Resistin was prolifically secreted by obese subcutaneous adipose tissue and impaired myotube thickness and nuclear fusion by activation of the classical NFκB pathway. Depletion of resistin from obese adipose tissue secretome restored myogenesis. Inhibition of the classical NFκB pathway protected myoblasts from the detrimental effect of resistin on myogenesis. Resistin also promoted intramyocellular lipid accumulation in myotubes and altered myotube metabolism by enhancing fatty acid oxidation and increasing myotube respiration and ATP production. In conclusion, resistin derived from human obese subcutaneous adipose tissue impairs myogenesis of human skeletal muscle, particularly older muscle, and alters muscle metabolism in developing myotubes. These findings may have important implications for the maintenance of muscle mass in older people with chronic inflammatory conditions, or older people who are obese or overweight.

Chen Z., Tao S., Li X., Yao Q.

Mitochondrial biogenesis deficits in neuronal cells are associated with the pathological progression of neurodegenerative diseases. Resistin, a secretory adipocytokine, possesses multiple physiological functions in diverse cells and tissues. However, the effects of resistin on mitochondrial biogenesis in neuronal cells are still elusive. In the current study, we found that resistin caused a sustainable decrease in mitochondrial contents, including mitochondrial DNA/nuclear DNA ratio (mtDNA/nDNA), mitochondrial mass, cytochrome b protein expression, and cytochrome c oxidase activity, which were correlated with "loss of mitochondrial function" including reduced mitochondrial respiration rate and ATP production in human SH-SY5Y neuronal cells. Indeed, resistin treatment destroyed the expression of peroxisome proliferator activator receptor gamma-coactivator 1α (PGC-1α), a master regulator of mitochondrial biogenesis, as well as its downstream target genes including nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM). Notably, overexpression of PGC-1α could completely rescue mitochondrial biogenesis and mitochondrial deficits induced by resistin. Mechanistically, inhibition of 5'-adenosine monophosphate-activated protein kinase (AMPK) was shown to mediate the inhibitory effects of resistin on mitochondrial biogenesis.

Boutari C., Perakakis N., Mantzoros C.S.

Marcelino-Rodríguez I., Almeida Gonzalez D., Alemán-Sánchez J.J., Brito Díaz B., Rodríguez Pérez M.D., Gannar F., Domínguez Coello S., Cuevas Fernández F.J., Cabrera de León A.

Aim Resistin is a cytokine related with inflammation and ischemic heart disease. Physical activity (PA) prevents chronic inflammation and ischemic heart disease. We studied the relationship of serum concentration of resistin with HDL cholesterol, a known biomarker of PA, and with different measures of PA, in a large sample of the general adult population in the Canary Islands. Methods Cross-sectional study of 6636 adults recruited randomly. We analyzed the correlation of resistin and HDL cholesterol with PA (as metabolic equivalent level [MET]), and fitted the results with linear and logistic regression models using adjustment for age, alcohol consumption and smoking. Results Mean resistin level was higher in women (p

Bednarska-Makaruk M., Graban A., Wiśniewska A., Łojkowska W., Bochyńska A., Gugała-Iwaniuk M., Sławińska K., Ługowska A., Ryglewicz D., Wehr H.

The aim of the study was to determine the role of adiponectin, leptin and resistin in various types of dementia and to investigate their association with inflammatory markers, insulin resistance and abdominal obesity. In 205 patients with dementia [89 with Alzheimer’s disease (AD), 47 with vascular dementia (VaD), 69 with mixed dementia (MD)], 113 persons with mild cognitive impairment and in 107 controls serum adiponectin, leptin and resistin levels, pro-inflammatory [interleukin-6 (IL-6), C-reactive protein (hsCRP) and chitotriosidase] and anti-inflammatory (25-OH vitamin D, HDL-cholesterol and paraoxonase 1) markers, as well as glucose metabolism parameters (glucose, insulin and HOMA-IR) were determined. In all-cause dementia adiponectin and resistin levels were significantly higher as compared to the controls; leptin levels did not show differences. Higher adiponectin levels concerned AD and MD, whereas higher resistin-VaD and MD. After stratification by abdominal obesity the differences in adiponectin levels remained significant in subjects without obesity. In all-cause dementia negative correlation of adiponectin with obesity, glucose metabolism parameters, IL-6 and hsCRP and positive correlation with HDL-cholesterol were found. Positive correlation of resistin with age, IL-6, hsCRP and chitotriosidase and negative correlation with HDL-cholesterol and paraoxonase 1 were stated. We conclude that dementia of neurodegenerative origin is characterized by elevated adiponectin levels, whereas dementia with vascular changes by increase of resistin. Association with inflammatory indicators may suggest the pro-inflammatory role of resistin in the development of dementia, especially in dementia of vascular mechanism. Identification of this novel biomarker may be important in preventing dementia.