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Genistein stimulates insulin sensitivity through gut microbiota reshaping and skeletal muscle AMPK activation in obese subjects
  1. Martha Guevara-Cruz1,
  2. Einar T Godinez-Salas1,
  3. Monica Sanchez-Tapia1,
  4. Gonzalo Torres-Villalobos2,
  5. Edgar Pichardo-Ontiveros1,
  6. Rocio Guizar-Heredia1,
  7. Liliana Arteaga-Sanchez1,
  8. Gerardo Gamba3,
  9. Raul Mojica-Espinosa4,
  10. Alejandro Schcolnik-Cabrera1,
  11. Omar Granados1,
  12. Adriana López-Barradas1,
  13. Ariana Vargas-Castillo1,
  14. Ivan Torre-Villalvazo1,
  15. Lilia G Noriega1,
  16. Nimbe Torres1,
  17. Armando R Tovar1
  1. 1Fisiologia de la Nutricion, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico
  2. 2Cirugía Experimental, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico
  3. 3Nefrología, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico
  4. 4Unidad de Microarreglos, Instituto Nacional de Medicina Genómica, Mexico
  1. Correspondence to Dr Armando R Tovar;{at}


Objective Obesity is associated with metabolic abnormalities, including insulin resistance and dyslipidemias. Previous studies demonstrated that genistein intake modifies the gut microbiota in mice by selectively increasing Akkermansia muciniphila, leading to reduction of metabolic endotoxemia and insulin sensitivity. However, it is not known whether the consumption of genistein in humans with obesity could modify the gut microbiota reducing the metabolic endotoxemia and insulin sensitivity.

Research design and methods 45 participants with a Homeostatic Model Assessment (HOMA) index greater than 2.5 and body mass indices of ≥30 and≤40 kg/m2 were studied. Patients were randomly distributed to consume (1) placebo treatment or (2) genistein capsules (50 mg/day) for 2 months. Blood samples were taken to evaluate glucose concentration, lipid profile and serum insulin. Insulin resistance was determined by means of the HOMA for insulin resistance (HOMA-IR) index and by an oral glucose tolerance test. After 2 months, the same variables were assessed including a serum metabolomic analysis, gut microbiota, and a skeletal muscle biopsy was obtained to study the gene expression of fatty acid oxidation.

Results In the present study, we show that the consumption of genistein for 2 months reduced insulin resistance in subjects with obesity, accompanied by a modification of the gut microbiota taxonomy, particularly by an increase in the Verrucomicrobia phylum. In addition, subjects showed a reduction in metabolic endotoxemia and an increase in 5′-adenosine monophosphate-activated protein kinase phosphorylation and expression of genes involved in fatty acid oxidation in skeletal muscle. As a result, there was an increase in circulating metabolites of β-oxidation and ω-oxidation, acyl-carnitines and ketone bodies.

Conclusions Change in the gut microbiota was accompanied by an improvement in insulin resistance and an increase in skeletal muscle fatty acid oxidation. Therefore, genistein could be used as a part of dietary strategies to control the abnormalities associated with obesity, particularly insulin resistance; however, long-term studies are needed.

  • fatty acid oxidation
  • insulin sensitivity
  • AMP-activated protein kinase
  • obesity

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  • Contributors ART developed the concept. MG-C, NT, and ART designed the clinical study. ETG-S, EP-O, RG-H, LA-S, and MG-C conducted the clinical study. GT-V performed the surgeries to obtain biopsies. MS-T performed the fecal gut microbiota analysis. RM-E, MG-C, AL-B, and RG-H conducted the microarray analysis. RG-H, OG, MG-C, IT-V, and LGN performed biochemical and molecular analyses. MG-C, MS-T, GG, RM-E, AS-C, AV-C, NT, and ART conducted the statistical analysis and interpreted the data. MG-C, AV-C, and NT generated the figures and tables. ART wrote the manuscript. The final manuscript was approved by all authors.

  • Funding This work was supported by the Consejo Nacional de Ciencia de Tecnología (México) (grant number 261843 to ART).

  • Competing interests MG-C, NT and ART are inventors of the patent application (number MX/a/2018/003668) filed with the Mexican Patent Office on the use of genistein as a modulator of the gut microbiota, leading to beneficial effects in obese subjects.

  • Patient consent for publication Not required.

  • Ethics approval This protocol was approved by the ethics committee of the Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran (reference 1099).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. Data are available upon request to the correspondent author.

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