Adiponectin preserves metabolic fitness during aging

Li, Na; Zhao, Shangang; Zhang, Zhuzhen; Zhu, Yi; Gliniak, Christy; Vishvanath, Lavanya; An, Yu; Wang, May Yun; Deng, Yingfeng; Zhu, Qianzheng; Shan, Bo; Sherwood, Amber; Onodera, Toshiharu; Öz, Orhan K.; Gordillo, Ruth; Gupta, Rana K.; Liu, Ming; Horváth, Tamas L.; Dixit, Vishwa Deep; Scherer, Philipp E.

doi:10.7554/elife.65108

Cited by 54 publications

(44 citation statements)

References 56 publications

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“…Adiponectin is an adipose-derived peptide hormone that activates lipid utilization and mitochondrial oxidative pathways in target tissues 22 , 23 . Adiponectin has been linked to metabolic dysfunction associated with obesity 24 , 25 and aging 26 , 27 , and has been implicated in the mechanisms of delayed aging by caloric restriction 28 , 29 . Adiponectin circulates as a multimer and the high molecular weight (HMW) isoform has been specifically linked to insulin sensitivity 30 .…”

Section: Resultsmentioning

confidence: 99%

Ceramides are early responders in metabolic syndrome development in rhesus monkeys

Smith

Schill

Gordillo

et al. 2022

Sci Rep

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Metabolic syndrome increases risk of complicating co-morbidities. Current clinical indicators reflect established metabolic impairment, preventing earlier intervention strategies. Here we show that circulating sphingolipids are altered in the very early stages of insulin resistance development. The study involved 16 paired overweight but healthy monkeys, one-half of which spontaneously developed metabolic syndrome over the course of 2 years. Importantly, animals did not differ in adiposity and were euglycemic throughout the study period. Using mass spectrometry, circulating sphingolipids, including ceramides and sphingomyelins, were detected and quantified for healthy and impaired animals at both time points. At time of diagnosis, several ceramides were significantly different between healthy and impaired animals. Correlation analysis revealed differences in the interactions among ceramides in impaired animals at diagnosis and pre-diagnosis when animals were clinically indistinguishable from controls. Furthermore, correlations between ceramides and early-stage markers of insulin resistance, diacylglycerols and non-esterified fatty acids, were distinct for healthy and impaired states. Regression analysis identifies coordinated changes in lipid handling across lipid classes as animals progress from healthy to insulin resistant. Correlations between ceramides and the adipose-derived adipokine adiponectin were apparent in healthy animals but not in the metabolically impaired animals, even in advance of loss in insulin sensitivity. These data suggest that circulating ceramides are clinically relevant in identifying disease risk independent of differences in adiposity, and may be important in devising preventative strategies.

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Section: Resultsmentioning

confidence: 99%

Ceramides are early responders in metabolic syndrome development in rhesus monkeys

Smith

Schill

Gordillo

et al. 2022

Sci Rep

Self Cite

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“…Circulating adiponectin concentrations appear to be decreased even further (Figure 1 - figure supplement 2D-2F), perhaps suggesting that flux of translated adiponectin protein is impaired through the secretion pathway. Of note, hypoadiponectinemia is associated with insulin resistance (Cook & Semple, 2010; N. Li et al, 2021), with discrepant reports on osteogenesis (Lewis, Edwards, Naylor, & McGettrick, 2021). Thus, we evaluated systemic metabolism in BMAd-Cre mice and found that body weight, glucose tolerance, WAT depot weights, and tibial trabecular and cortical bone variables are unaffected by this degree of hypoadiponectinemia (Figure 1 - figure supplement 2G-2P).…”

Section: Resultsmentioning

confidence: 99%

Lipolysis of bone marrow adipocytes is required to fuel bone and the marrow niche during energy deficits

MacDougald

Bowers

et al. 2022

Preprint

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To investigate roles for bone marrow adipocyte (BMAd) lipolysis in bone homeostasis, we created a BMAd-specific Cre mouse model in which we knocked out adipose triglyceride lipase (ATGL, Pnpla2). BMAd-Pnpla2-/- mice have impaired BMAd lipolysis, and increased size and number of BMAds at baseline. Although energy from BMAd lipid stores is largely dispensable when mice are fed ad libitum, BMAd lipolysis is necessary to maintain myelopoiesis and bone mass under caloric restriction. BMAd-specific Pnpla2 deficiency compounds the effects of caloric restriction on loss of trabecular bone, likely due to impaired osteoblast expression of collagen genes and reduced osteoid synthesis. RNA sequencing analysis of bone marrow adipose tissue reveals that caloric restriction induces dramatic elevations in extracellular matrix organization and skeletal development genes, and energy from BMAd is required for these adaptations. BMAd-derived energy supply is also required for bone regeneration upon injury, and maintenance of bone mass with cold exposure.

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“…For two of the three proteins that were decreased in T2D compared to controls, our findings here are in accord with the findings reported in IGT, where adiponectin and endocan were two of the top differentially expressed proteins that were found to be decreased in those with IGT and reduced β-cell sensitivity [ 15 ]. Low adiponectin levels have previously been linked to insulin resistance and β-cell function [ 24 , 25 , 26 ]; adiponectin levels are inversely correlated with body fat and have been purported to be a biomarker of adipose tissue health [ 4 , 27 , 28 ]. Endocan is a proteoglycan expressed in endothelial cells and adipocytes and low levels are associated with inflammation and visceral obesity [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and Prognostic Protein Biomarkers of β-Cell Function in Type 2 Diabetes and Their Modulation with Glucose Normalization

et al. 2022

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Development of type-2 diabetes(T2D) is preceded by β-cell dysfunction and loss. However, accurate measurement of β-cell function remains elusive. Biomarkers have been reported to predict β-cell functional decline but require validation. Therefore, we determined whether reported protein biomarkers could distinguish patients with T2D (onset < 10-years) from controls. A prospective, parallel study in T2D (n = 23) and controls (n = 23) was undertaken. In T2D subjects, insulin-induced blood glucose normalization from baseline 7.6 ± 0.4 mmol/L (136.8 ± 7.2 mg/dL) to 4.5 ± 0.07 mmol/L (81 ± 1.2 mg/dL) was maintained for 1-h. Controls were maintained at 4.9 ± 0.1 mmol/L (88.2 ± 1.8 mg/dL). Slow Off-rate Modified Aptamer (SOMA) -scan plasma protein measurement determined a 43-protein panel reported as diagnostic and/or prognostic for T2D. At baseline, 9 proteins were altered in T2D. Three of 13 prognostic/diagnostic proteins were lower in T2D: Adiponectin (p < 0.0001), Endocan (p < 0.05) and Mast/stem cell growth factor receptor-Kit (KIT) (p < 0.01). Two of 14 prognostic proteins [Cathepsin-D (p < 0.05) and Cadherin-E (p < 0.005)], and four of 16 diagnostic proteins [Kallikrein-4 (p = 0.001), Aminoacylase-1 (p = 0.001), Insulin-like growth factor-binding protein-4 (IGFBP4) (p < 0.05) and Reticulon-4 receptor (RTN4R) (p < 0.001)] were higher in T2D. Protein levels were unchanged following glucose normalization in T2D. Our results suggest that a focused biomarker panel may be useful for assessing β-cell dysfunction and may complement clinical decision-making on insulin therapy. Unchanged post-glucose normalization levels indicate these are not acute-phase proteins or affected by glucose variability.

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Adiponectin preserves metabolic fitness during aging

Cited by 54 publications

References 56 publications

Ceramides are early responders in metabolic syndrome development in rhesus monkeys

Ceramides are early responders in metabolic syndrome development in rhesus monkeys

Lipolysis of bone marrow adipocytes is required to fuel bone and the marrow niche during energy deficits

Diagnostic and Prognostic Protein Biomarkers of β-Cell Function in Type 2 Diabetes and Their Modulation with Glucose Normalization

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