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Interleukin 1 receptor-associated kinase 1, 4 (IRAK 1/4) inhibitor exerts anti-inflammatory and immuno-modulatory effects; however, its role in high-fat diet-induced vascular dysfunction and cognitive impairment is not known, and therefore investigated in the present study. Animals were fed either a high-fat diet (60% Kcal fat) or a chow diet (10% Kcal fat) for 12 weeks to induce hyperlipidemia and weight gain. High-fat diet-fed animals were then treated with vehicle, IRAK1/4 inhibitor (2.2 mg/kg, i.p.) and a reference drug, Orlistat (20 mg/kg, oral gavage), for 4 additional weeks. Protein levels were assessed by ELISA or Western blotting, and mRNA by RT-PCR. IRAK1/4 inhibitor and reference drug, Orlistat treatment, prevented HFD-induced increase in body weight gain, fasting blood glucose and plasma lipids, improved discrimination between the familiar and the novel arm in the Y-Maze test, alleviated percent avoidance in two-way active avoidance, and freezing percent in contextual fear conditioning test. The treatments attenuated the levels of systemic inflammatory cytokines IL-1β, CRP, as well as TNF-α, IL-6 and protein expression of Iba-1, GFAP, HIF-1α, and restored the BDNF levels in the pre-frontal cortex of HFD-fed treated mice. IRAK 1/4 inhibitor exerted these effects by blocking proteasomal degradation of IκB-α protein in the pre-frontal cortex of HFD-treated mice. In addition, the treatments prevented HFD-induced increase in vascular ICAM-1, VCAM-1, MCP-1, COX-1 and COX-2 mRNA expression, and restored vascular eNOS mRNA levels as well as the Acetylcholine (300 ρM-300 μM) induced relaxations of PE (1 µM) pre-contracted aortic rings. IRAK1/4 inhibitor attenuates HFD-induced inflammation, vascular dysfunction and cognitive impairment in obese mice. Show less

High-fat diet (HFD)-induced obesity impairs cognition and hippocampal neurogenesis, linked to reduced metabolic flexibility between mitochondrial fatty acid β-oxidation (FAO) and cytosolic de novo lipogenesis (DNL). It is not fully understood if switching to a high-carbohydrate diet (HCD) or a ketogenic diet (KD) could reverse these HFD-induced deficits, or if they do so through different mechanisms. Male C57BL/6J mice received HFD for 8 weeks to induce obesity. Mice were then either maintained on the HFD or switched to an HCD or KD for an additional 8 weeks. We evaluated systemic metabolism (body weight, serum biochemistry), tissue-specific metabolic remodeling (RNA-seq, histology, RT-qPCR, Western blot) and cognitive function (Y-maze test, novel object recognition test). Both HCD and KD interventions reversed HFD‑induced systemic abnormalities, including reducing ALT/AST, cholesterol, and LDL, and attenuating hepatic steatosis and adipocyte hypertrophy. Metabolically, KD markedly increased β‑hydroxybutyrate, whereas HCD showed a distinct triglyceride profile. Both diets improved hippocampus-dependent working and recognition memory. Hippocampal RNA‑seq revealed diet-specific mechanisms. HCD enriched anabolic processes, including upregulation of glucose transporters (Glut 1, 2, 3, 4) and DNL pathway (ACLY-ACC-FASN-SCD1). Conversely, KD enriched AMPK signaling, increasing monocarboxylate transporters (Mct 1, 2, 4) for ketone uptake and activating the neurotrophic AMPK-ERK-CREB-BDNF pathway. In conclusion, post-HFD switching to HCD or KD restores hippocampal structure and cognition via complementary mechanisms. HCD drives a substrate-centric, lipogenic program supporting proliferation, whereas KD engages a signaling-centric, neurotrophic program enhancing plasticity. Metabolic flexibility is a promising target for obesity-associated cognitive decline. Show less