Obesity and MASLD (NAFLD) are chronic, low-grade systemic inflammatory diseases resulting from complex interactions among diet, adipose tissue, gut microbiota, liver, muscle, pancreas, and the brain. Central to this integrative framework are AA and other polyunsaturated fatty acids (PUFAs), which regulate inflammation, insulin sensitivity, neuroendocrine signaling, and energy homeostasis.Excess consumption of energy-dense foods rich in saturated and trans fats leads to adipocyte hypertrophy, altered membrane fluidity, increased antigenicity, and enhanced recruitment of macrophages and T cells into adipose tissue. These changes promote the sustained release of pro-inflammatory cytokines TNF-α, IL-6, MIF, and CRP, contributing to insulin resistance, metabolic syndrome, and MASLD (NAFLD). In contrast, adequate availability of GLA, DGLA, AA, EPA, and DHA improves cell membrane dynamics and serves as a substrate for anti-inflammatory and pro-resolving lipid mediators, including lipoxins, resolvins, protectins, maresins, and nitrolipids, which suppress inflammatory signaling and enhance adiponectin production.Abdominal obesity can be considered a localized glucocorticoid excess state driven by increased adipose 11β-hydroxysteroid dehydrogenase-1 (11β-HSD-1) activity, linking visceral fat accumulation to insulin resistance, altered PPAR signaling, and chronic inflammation. Suppression of 11β-HSD-1, increased PUFA intake, and exercise can ameliorate these abnormalities.Gut microbiota and their short-chain fatty acids influence inflammation, leptin signaling, incretin secretion, and lipid metabolism, while PUFAs-including AA-activate gut-brain-liver neural circuits via vagal pathways and G protein-coupled receptors to regulate satiety, insulin secretion, and hepatic glucose production. This chapter also emphasizes the role of hypothalamic factors, particularly BDNF, in integrating nutritional, hormonal, and inflammatory signals.In summary, AA and related PUFAs are critical modulators of inflammation resolution, neuroendocrine control, and metabolic balance, offering a unifying mechanistic framework for the prevention and management of obesity and its associated metabolic disorders.
