The Influence of Obesity and Associated Fatty Acids on Placental Inflammation

Abstract

Purpose: Maternal obesity, affecting nearly 1 in 4 pregnancies, is associated with increased circulating saturated fatty acids, such as palmitate. These fatty acids are implicated in placental inflammation, which may in turn exacerbate both maternal-fetal tolerance and responses to pathogens, such as group B Streptococcus. In this review, we address the question, "How do obesity and associated fatty acids influence placental inflammation?"

Methods: In this narrative review, we searched PubMed and Google Scholar using combinations of the key words placental inflammation or pregnancy and lipids, fatty acids, obesity, palmitate, or other closely related search terms. We also used references found within these articles that may have been absent from our original search queries. We analyzed methods and key results of these articles to compare and contrast their findings, which were occasionally at odds with each other.

Findings: Although obesity can be studied as a whole, complex phenomena with in vivo mouse models and human samples from patients with obesity, in vitro modeling often relies on the treatment of cells or tissues with ≥1 fatty acids and occasionally other compounds (eg, glucose and insulin). We found that palmitate, most commonly used in vitro to recreate hallmarks of obesity, induces apoptosis, oxidative stress, mitochondrial dysfunction, autophagy defects, and inflammasome activation in many placental cell types. We compare this to in vivo models of obesity wherever possible. We found that obesity as a whole may have more complex regulation of these phenomena (apoptosis, oxidative stress, mitochondrial dysfunction, autophagy defects, and inflammasome activation) compared with in vitro models of fatty acid treatment (primarily palmitate) because of the presence of unsaturated fatty acids (ie, oleate), which may have anti-inflammatory effects.

Implications: The interaction of unsaturated fatty acids with saturated fatty acids may ameliorate many inflammatory effects of saturated fatty acids alone, which complicates interpretation of in vitro studies that focus on a particular fatty acid in isolation. This complication may explain why certain studies of obesity in vivo have differing outcomes from studies of specific fatty acids in vitro.

Keywords: endoplasmic reticulum stress; obesity; palmitate; placental inflammation.

Figure 1.. Chemical representations of fatty acids included in this review.

(A) The saturated fatty acid palmitate features heavily into models of obesity, and stearate is occasionally used as a comparison. (B) The mono-unsaturated fat oleate can often act as a counter to the inflammatory properties of palmitate; the monounsaturated fatty acid palmitoleic acid and polyunsaturated fatty acids linoleic acid are used as comparisons. The omega-3 fatty acid docosahexaenoic acid (DHA, or one of its major sources, fish oil) has been frequently observed to be anti-inflammatory, and arachidonic acid plays a major role in fetal development. (C) Some speculation exists that palmitate acts as a ligand for Toll-like receptor 4 (TLR4) because it resembles portions of bacterial lipopolysaccharide (LPS)^, , the canonical agonist for TLR4, although this remains controversial.

Figure 2.. The lipid milieu in circulation during obesity features multiple saturated and unsaturated fatty acids, which can activate or suppress multiple inflammatory or inflammation-adjacent cellular pathways.

Palmitate can decrease the anti-inflammatory lipid droplet formation, while oleate can counter the effect of palmitate on lipid droplet formation in syncytiotrophoblasts and trophoblasts^–. Excess palmitate can increase key autophagosome gene expression, but suppresses fusion of the autophagosome and lysosome, thus causing autophagy defects, the buildup of these products can induce ER stress. Mitochondrial dysfunction and reactive oxygen species formation can also activate the ER stress pathway. Unmitigated ER stress can trigger apoptotic cell death pathways, as can mitochondrial dysfunction and inflammasome activation. Diagram created using BioRender.