Low Neonatal Plasma n-6/n-3 PUFA Ratios Regulate Offspring Adipogenic Potential and Condition Adult Obesity Resistance

Diabetes. 2018 Apr;67(4):651-661. doi: 10.2337/db17-0890. Epub 2017 Nov 14.


Adipose tissue expansion progresses rapidly during postnatal life, influenced by both prenatal maternal factors and postnatal developmental cues. The ratio of omega-6 (n-6) relative to n-3 polyunsaturated fatty acids (PUFAs) is believed to regulate perinatal adipogenesis, but the cellular mechanisms and long-term effects are not well understood. We lowered the fetal and postnatal n-6/n-3 PUFA ratio exposure in wild-type offspring under standard maternal dietary fat amounts to test the effects of low n-6/n-3 ratios on offspring adipogenesis and adipogenic potential. Relative to wild-type pups receiving high perinatal n-6/n-3 ratios, subcutaneous adipose tissue in 14-day-old wild-type pups receiving low n-6/n-3 ratios had more adipocytes that were smaller in size; decreased Pparγ2, Fabp4, and Plin1; several lipid metabolism mRNAs; coincident hypermethylation of the PPARγ2 proximal promoter; and elevated circulating adiponectin. As adults, offspring that received low perinatal n-6/n-3 ratios were diet-induced obesity (DIO) resistant and had a lower positive energy balance and energy intake, greater lipid fuel preference and non-resting energy expenditure, one-half the body fat, and better glucose clearance. Together, the findings support a model in which low early-life n-6/n-3 ratios remodel adipose morphology to increase circulating adiponectin, resulting in a persistent adult phenotype with improved metabolic flexibility that prevents DIO.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / cytology
  • Adipogenesis*
  • Adiponectin / metabolism
  • Animals
  • Animals, Newborn
  • Blood Glucose / metabolism*
  • Cell Proliferation
  • Cell Size
  • DNA Methylation
  • Diet, High-Fat
  • Dietary Fats
  • Energy Intake
  • Energy Metabolism
  • Fatty Acid-Binding Proteins / metabolism
  • Fatty Acids, Omega-3 / blood*
  • Fatty Acids, Omega-6 / blood*
  • Female
  • Lipid Metabolism*
  • Mice
  • Obesity / blood
  • Obesity / epidemiology*
  • PPAR gamma / metabolism
  • Perilipin-1 / metabolism
  • Pregnancy
  • Prenatal Exposure Delayed Effects / blood
  • Prenatal Exposure Delayed Effects / epidemiology*
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Risk Factors


  • Adiponectin
  • Adipoq protein, mouse
  • Blood Glucose
  • Dietary Fats
  • Fabp4 protein, mouse
  • Fatty Acid-Binding Proteins
  • Fatty Acids, Omega-3
  • Fatty Acids, Omega-6
  • PPAR gamma
  • Perilipin-1
  • Plin1 protein, mouse
  • RNA, Messenger