Differential effects of obesogenic diets components on hypothalamic leptin resistance: a narrative review

Abstract The escalating obesity pandemic is intrinsically linked to Western dietary patterns, which induce hypothalamic leptin resistance, a paradoxical state where the hormone fails to regulate energy homeostasis despite hyperleptinemia. This narrative review synthesizes current evidence regarding the differential impact of specific obesogenic diet components on central leptin sensitivity. Was examined how diet-induced redox imbalance and chronic inflammation, particularly through endoplasmic reticulum stress and SOCS3 upregulation, disrupt the canonical JAK2/STAT3 signaling pathway. Crucially, evidence suggests that macronutrients operate via distinct pathogenic mechanisms. Excessive intake of simple sugars, notably fructose and liquid sugars, precipitates resistance independent of weight gain by activating the hexosamine biosynthetic pathway, leading to O-GlcNAcylation of signaling intermediates and blunted STAT3 phosphorylation. Conversely, while saturated fats drive inflammation via Toll-like receptors, they primarily impair leptin action by hindering its transport across the blood-brain barrier rather than solely disrupting intracellular cascades. Furthermore, the synergistic consumption of sugars and fats accelerates the onset of both peripheral and central resistance, exacerbating adiposity more potently than either component alone. By dissecting these nutrient-specific pathways, this review provides a comprehensive understanding of how obesogenic diets structurally and functionally compromise hypothalamic metabolic control, highlighting that resistance is not merely a consequence of fat mass expansion but of specific dietary composition.