Surgery-Induced Weight Loss Is Associated With the Downregulation of Genes Targeted by MicroRNAs in Adipose Tissue

Ortega, Francisco; Mercader, Josep M.; Moreno-Navarrete, José María; Nonell, Lara; Puigdecanet, Eulàlia; Rodriquez-Hermosa, José I.; Rovira, Oscar; Xifra, Gemma; Guerra, Ester; Moreno, María; Mayas, Dolores; Moreno-Castellanos, Natalia; Fernández-Formoso, José Antonio; Ricart, Wifredo; Tinahones, Francisco J.; Torrents, David; Malagón, Marı́a M.; Fernández-Real, José Manuel

doi:10.1210/jc.2015-2357

Cited by 52 publications

(70 citation statements)

References 35 publications

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“…The use of systems biology-based approaches (such as genomics, transcriptomics, proteomics and lipidomics) permits a molecular fingerprinting of these tissues. Transcriptomics revealed differentially expressed genes belonging to adipogenesis and lipid metabolism ontogenies both in vivo [4][5][6] and in cells in vitro [7]. This fits with a differential pattern of protein expression, with locationspecific traits in proteins involved in lipid oxidation-reduction and transport [8].…”

Section: Introductionsupporting

confidence: 56%

“…This cohort included 70 paired SAT and VAT samples (eight non-obese and 62 obese participants). In a second cohort of morbidly obese (BMI >35 kg/m 2 ) individuals with different degrees of insulin activity (measured using hyperinsulinaemic-euglycaemic clamp [6], as detailed in the ESM Methods), 44 paired SAT and VAT samples (cohort 2) were studied ( Table 1). The participants were recruited at the Endocrinology Service of the Hospital of Girona Dr Josep Trueta.…”

Section: Recruitment Of Donors For Adipose Tissue Samplesmentioning

confidence: 99%

“…Isolated mature adipocytes and SVF were stored at −80°C for gene expression analysis. [6]. Inclusion criteria were age 30-60 years, BMI ≥ 35 kg/m 2 and ability to understand the study protocol.…”

Section: Recruitment Of Donors For Adipose Tissue Samplesmentioning

confidence: 99%

“…RNA purification, gene expression procedures and analyses were performed, as detailed in electronic supplementary material (ESM) Methods and previously described [6,14,15].…”

Section: Rna Expressionmentioning

confidence: 99%

“…To further study the potential importance of PLP in adipogenesis at a functional level, SAT PDXK gene expression was studied according to systemic insulin sensitivity (measured using hyperinsulinaemic-euglycaemic clamp), confirming a positive association (Table 4). Bariatric surgery-induced weight loss, which resulted in a significant increase in the expression of adipogenic genes [6], also led to increased PDXK mRNA levels gene expression (Table 5) …”

Section: Pdxk Is Implicated In Adipogenic Differentiation In Human Admentioning

confidence: 99%

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Metabolomics uncovers the role of adipose tissue PDXK in adipogenesis and systemic insulin sensitivity

et al. 2016

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Aims/hypothesis We aimed to investigate the potential mechanisms involved in the compromised adipogenesis of visceral (VAT) vs subcutaneous adipose tissue (SAT) using comparative metabolomics. Based on the differentially identified metabolites, we focused on the relationship between the active form of vitamin B 6 (pyridoxal 5-phosphate [PLP]), known to be generated through pyridoxal kinase (PDXK), and adipogenesis. Methods Non-targeted metabolomics analyses were performed in paired VAT and SAT (n = 14, discovery cohort). PDXK gene expression was evaluated in two validation cohorts of paired SAT and VAT samples in relation to obesity status and insulin sensitivity, and mechanistically after weight loss in vivo and in 3T3-L1 cells in vitro.Results Comparative metabolomics showed that PLP was significantly decreased in VAT vs SAT. Concordantly, PDXK mRNA levels were significantly decreased in VAT vs SAT, specifically in adipocytes. The decrease was specially marked in obese individuals. PDXK mRNA levels showed a strong association with adipogenic, lipid-droplet-related and lipogenic genes. At a functional level, systemic insulin sensitivity positively associated with PDXK expression, and surgically-induced weight loss (improving insulin sensitivity) led to increased SAT PDXK mRNA levels in parallel with adipogenic genes. In human pre-adipocytes, PDXK mRNA levels increased during adipocyte differentiation and after administration of peroxisome proliferator-activated receptor-γ agonists, and decreased under inflammatory stimuli. Mechanistic studies in 3T3-L1 cells showed that PLP administration resulted in increased adipogenic mRNA markers during early adipogenesis, whereas the PLP antagonist 4-deoxypyridoxine exerted opposite effects. Conclusions/interpretation Overall, these results support the notion that in situ production of PLP is required for physiological adipogenesis.

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Section: Introductionsupporting

confidence: 56%

Section: Recruitment Of Donors For Adipose Tissue Samplesmentioning

confidence: 99%

Section: Recruitment Of Donors For Adipose Tissue Samplesmentioning

confidence: 99%

“…RNA purification, gene expression procedures and analyses were performed, as detailed in electronic supplementary material (ESM) Methods and previously described [6,14,15].…”

Section: Rna Expressionmentioning

confidence: 99%

Section: Pdxk Is Implicated In Adipogenic Differentiation In Human Admentioning

confidence: 99%

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Metabolomics uncovers the role of adipose tissue PDXK in adipogenesis and systemic insulin sensitivity

et al. 2016

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Therapeutic Effects of Butyrate on Pediatric Obesity

et al. 2022

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ImportanceThe pediatric obesity disease burden imposes the necessity of new effective strategies.ObjectiveTo determine whether oral butyrate supplementation as an adjunct to standard care is effective in the treatment of pediatric obesity.Design, Setting, and ParticipantsA randomized, quadruple-blind, placebo-controlled trial was performed from November 1, 2020, to December 31, 2021, at the Tertiary Center for Pediatric Nutrition, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy. Participants included children aged 5 to 17 years with body mass index (BMI) greater than the 95th percentile.InterventionsStandard care for pediatric obesity supplemented with oral sodium butyrate, 20 mg/kg body weight per day, or placebo for 6 months was administered.Main Outcomes and MeasuresThe main outcome was the decrease of at least 0.25 BMI SD scores at 6 months. The secondary outcomes were changes in waist circumference; fasting glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, ghrelin, microRNA-221, and interleukin-6 levels; homeostatic model assessment of insulin resistance (HOMA-IR); dietary and lifestyle habits; and gut microbiome structure. Intention-to-treat analysis was conducted.ResultsFifty-four children with obesity (31 girls [57%], mean [SD] age, 11 [2.91] years) were randomized into the butyrate and placebo groups; 4 were lost to follow-up after receiving the intervention in the butyrate group and 2 in the placebo group. At intention-to-treat analysis (n = 54), children treated with butyrate had a higher rate of BMI decrease greater than or equal to 0.25 SD scores at 6 months (96% vs 56%, absolute benefit increase, 40%; 95% CI, 21% to 61%; P &lt; .01). At per-protocol analysis (n = 48), the butyrate group showed the following changes as compared with the placebo group: waist circumference, −5.07 cm (95% CI, −7.68 to −2.46 cm; P &lt; .001); insulin level, −5.41 μU/mL (95% CI, −10.49 to −0.34 μU/mL; P = .03); HOMA-IR, −1.14 (95% CI, −2.13 to −0.15; P = .02); ghrelin level, −47.89 μg/mL (95% CI, −91.80 to −3.98 μg/mL; P &lt; .001); microRNA221 relative expression, −2.17 (95% CI, −3.35 to −0.99; P &lt; .001); and IL-6 level, −4.81 pg/mL (95% CI, −7.74 to −1.88 pg/mL; P &lt; .001). Similar patterns of adherence to standard care were observed in the 2 groups. Baseline gut microbiome signatures predictable of the therapeutic response were identified. Adverse effects included transient mild nausea and headache reported by 2 patients during the first month of butyrate intervention.Conclusions and RelevanceOral butyrate supplementation may be effective in the treatment of pediatric obesity.Trial RegistrationClinicalTrials.gov Identifier: NCT04620057

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A microRNA Cluster Controls Fat Cell Differentiation and Adipose Tissue Expansion By Regulating SNCG

et al. 2021

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The H19X‐encoded miR‐424(322)/503 cluster regulates multiple cellular functions. Here, it is reported for the first time that it is also a critical linchpin of fat mass expansion. Deletion of this miRNA cluster in mice results in obesity, while increasing the pool of early adipocyte progenitors and hypertrophied adipocytes. Complementary loss and gain of function experiments and RNA sequencing demonstrate that miR‐424(322)/503 regulates a conserved genetic program involved in the differentiation and commitment of white adipocytes. Mechanistically, it is demonstrated that miR‐424(322)/503 targets γ‐Synuclein (SNCG), a factor that mediates this program rearrangement by controlling metabolic functions in fat cells, allowing adipocyte differentiation and adipose tissue enlargement. Accordingly, diminished miR‐424(322) in mice and obese humans co‐segregate with increased SNCG in fat and peripheral blood as mutually exclusive features of obesity, being normalized upon weight loss. The data unveil a previously unknown regulatory mechanism of fat mass expansion tightly controlled by the miR‐424(322)/503 through SNCG.

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Surgery-Induced Weight Loss Is Associated With the Downregulation of Genes Targeted by MicroRNAs in Adipose Tissue

Abstract: Current findings suggest impaired miRNA target gene expression in obese AT in close association with inflammation, both improving after weight loss.

Cited by 52 publications

References 35 publications

Metabolomics uncovers the role of adipose tissue PDXK in adipogenesis and systemic insulin sensitivity

Metabolomics uncovers the role of adipose tissue PDXK in adipogenesis and systemic insulin sensitivity

Therapeutic Effects of Butyrate on Pediatric Obesity

A microRNA Cluster Controls Fat Cell Differentiation and Adipose Tissue Expansion By Regulating SNCG

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