A randomised trial examining inflammatory signaling in acutely induced hyperinsulinemia and hyperlipidemia in normal weight women-the reprometabolic syndrome

PLoS One. 2021 Mar 25;16(3):e0247638. doi: 10.1371/journal.pone.0247638. eCollection 2021.


Context: Obesity, is a state of chronic inflammation, characterized by elevated lipids, insulin resistance and relative hypogonadotropic hypogonadism. We have defined the accompanying decreased Luteinizing Hormone (LH), Follicle-Stimulating Hormone (FSH), ovarian steroids and reduced pituitary response to Gonadotropin-releasing Hormone (GnRH) as Reprometabolic syndrome, a phenotype that can be induced in healthy normal weight women (NWW) by acute infusion of free fatty acids and insulin.

Objective: To identify potential mediators of insulin and lipid-related reproductive endocrine dysfunction.

Design, setting, participants: Secondary analysis of crossover study of eumenorrheic reproductive aged women of normal Body Mass Index (BMI) (<25 kg/m2) at an academic medical center.

Intervention: Participants underwent 6-hour infusions of either saline/heparin or insulin plus fatty acids (Intralipid plus heparin), in the early follicular phase of sequential menstrual cycles, in random order. Euglycemia was maintained by glucose infusion. Frequent blood samples were obtained.

Main outcome measures: Pooled serum from each woman was analyzed for cytokines, interleukins, chemokines, adipokines, Fibroblast Growth Factor-21 (FGF-21) and markers of endoplasmic reticulum (ER) stress (CHOP and GRP78). Wilcoxon signed-rank tests were used to compare results across experimental conditions.

Results: Except for Macrophage Inflammatory Protein-1β (MIP-1β), no significant differences were observed in serum levels of any of the inflammatory signaling or ER stress markers tested.

Conclusion: Acute infusion of lipid and insulin, to mimic the metabolic syndrome of obesity, was not associated with an increase in inflammatory markers. These results imply that the endocrine disruption and adverse reproductive outcomes of obesity are not a consequence of the ambient inflammatory environment but may be mediated by direct lipotoxic effects on the hypothalamic-pituitary-ovarian (HPO) axis.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Academic Medical Centers
  • Adolescent
  • Adult
  • Body Mass Index
  • Cross-Over Studies
  • Cytokines / genetics
  • Cytokines / metabolism
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress
  • Fat Emulsions, Intravenous / administration & dosage
  • Fatty Acids, Nonesterified / administration & dosage*
  • Female
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / metabolism
  • Follicle Stimulating Hormone / genetics
  • Follicle Stimulating Hormone / metabolism
  • Gene Expression
  • Genetic Fitness / drug effects
  • Genetic Fitness / genetics
  • Glucose Clamp Technique
  • Gonadotropin-Releasing Hormone / genetics
  • Gonadotropin-Releasing Hormone / metabolism
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Humans
  • Hyperinsulinism / chemically induced
  • Hyperinsulinism / genetics
  • Hyperinsulinism / metabolism*
  • Hyperinsulinism / pathology
  • Hyperlipidemias / chemically induced
  • Hyperlipidemias / genetics
  • Hyperlipidemias / metabolism*
  • Hyperlipidemias / pathology
  • Insulin / administration & dosage*
  • Luteinizing Hormone / genetics
  • Luteinizing Hormone / metabolism
  • Metabolic Syndrome / chemically induced
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / metabolism*
  • Metabolic Syndrome / pathology
  • Pituitary Gland / drug effects
  • Pituitary Gland / metabolism
  • Signal Transduction*
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism


  • Cytokines
  • DDIT3 protein, human
  • Endoplasmic Reticulum Chaperone BiP
  • FGF21 protein, human
  • Fat Emulsions, Intravenous
  • Fatty Acids, Nonesterified
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Insulin
  • Transcription Factor CHOP
  • Gonadotropin-Releasing Hormone
  • Fibroblast Growth Factors
  • Luteinizing Hormone
  • Follicle Stimulating Hormone