Background/Objective: Zinc deficiency is common worldwide and has been linked to reduced growth and immune function, increased risk of and slower recovery from infections, and increased risk of non-communicable diseases. To address the issue, zinc biofortification of wheat has been proposed as a sustainable approach to increase dietary zinc intake in countries like Pakistan, where zinc deficiency rates are high and wheat is the primary staple crop. Since plasma zinc concentration (PZC) does not reliably respond to small changes in zinc intake, biomarkers sensitive to small changes in zinc intake achievable though biofortification are needed. Activity indices for zinc-dependent metabolic steps of desaturation and elongation of omega-6 fatty acids (FAs) have been proposed as sensitive zinc biomarkers. Oxylipin metabolites of polyunsaturated FAs may also respond to changes in zinc intake and further mediate metabolic response to oxidative stress. The objective of the current study was to assess the effects of consuming zinc-biofortified wheat flour on plasma markers of fatty acid (FA) metabolism in females aged 10–16 years. Methods: A nested secondary analysis was conducted in samples from a double-blind, cluster-randomized controlled trial conducted in rural Pakistan, whereparticipants (n = 517) consumed either zinc-biofortified wheat flour or control flour for 25 weeks. Total plasma FAs and oxylipins were measured by liquid chromatography tandem mass spectrometry (LC–MS/MS). Activity indices were estimated from the ratios of product to precursor FAs. Results: Except for docosahexaenoic acid (DHA, p < 0.05), no significant intervention effect was observed on plasma FAs and FA activity index endpoints. Zinc-biofortified wheat intake reduced pro-inflammatory oxylipins and biomarkers of oxidative stress, 5-HETE (p < 0.05), 9-HETE (p < 0.05), 11-HETE (p < 0.05), and 15-HETE (p < 0.05), compared with the control. However, after adjustment for multiple comparisons, none of the intervention effects remained significant. Conclusions: Further study of the responsiveness and specificity of plasma oxylipins to changes in zinc intake is warranted.

Due to its unique chemical nature, zinc is indispensable to diverse functional roles in protein structure, catalysis, and the dynamic regulation of metabolic processes. In support of zinc-dependent metabolic functions, the zinc content of peripheral blood plasma turns over in exchange with cells on the order of 100-fold daily. Although zinc deficiency is well-known for its effects in reducing child growth and impairing immune function, a growing body of evidence has implicated zinc intake and plasma zinc concentration in the complex etiological web of metabolic disease. In turn, stresses linked with the progression of metabolic disease interfere with protein–zinc binding and accelerate zinc loss from the body. We summarize evidence connecting zinc with metabolic disease, discuss the effects of metabolic disease on zinc homeostasis, and suggest areas for future research to integrate knowledge of zinc metabolism with efforts to prevent and treat metabolic disease.