Background/Objectives: Goto-Kakizaki (GK) rats exhibit insulin resistance and type 2 diabetes mellitus (T2DM) without obesity. This study explored the effects of ω-3 fatty acid supplementation on T lymphocyte polarization in Wistar (WT) and GK rats. Methods: They were administered ω-3 fatty acid-rich fish oil (FO) containing eicosapentaenoic (540 mg/g) and docosahexaenoic acids (100 mg/g) by oral gavage at 2 g/kg, thrice a week for 8 weeks. The control groups (WT CT and GK CT) received the same volume of water. The following groups were investigated: GK CT, n = 14; GK ω-3, n = 15; Wistar CT, n = 15; and Wistar ω-3, n = 11. Glucose and insulin tolerance tests (GTT and ITT) were performed. Fasting plasma insulinemia and glycemia were measured. After euthanasia, the lymphocytes were extracted from the mesenteric lymph nodes. Results: The results showed that GK rats supplemented with FO had significantly improved glucose tolerance and insulin sensitivity (kITT). It also promoted greater polarization of lymphocytes toward T regulatory (Treg) features and a reduction in Th1 and Th17 profiles. Additionally, the GK ω-3 group exhibited lower cell proliferation, decreased pro-inflammatory cytokines, and increased IL-10 levels compared to the GK control. Conclusions: In conclusion, FO supplementation benefited GK rats by improving glucose intolerance, suppressing insulin resistance, and modulating lymphocytes toward Treg polarization.

Brain glucose hypometabolism and neuroinflammation are early pathogenic manifestations in neurological disorders. Neuroinflammation may also disrupt leptin signaling, an adipokine that centrally regulates appetite and energy balance by acting on the hypothalamus and exerting neuroprotection in the hippocampus. The Goto-Kakizaki (GK) rat is a non-obese type 2 diabetes mellitus (T2DM) animal model used to investigate diabetes-associated molecular mechanisms without obesity jeopardizing effects. Wistar and GK rats received the maintenance adult rodent diet. Also, an additional control group of Wistar rats received a high-fat and high-sugar diet (HFHS) provided by free consumption of condensed milk. All diets and water were provided ad libitum for eight weeks. Brain glucose uptake was evaluated by 2-deoxy-2-[fluorine-18] fluoro-D-glucose under basal (saline administration) or stimulated (CL316,243, a selective β3-AR agonist) conditions. The animals were fasted for 10-12 h, anesthetized, and euthanized. The brain was quickly dissected, and the hippocampal area was sectioned and stored at -80°C in different tubes for protein and RNA analyses on the same animal. GK rats exhibited attenuated brain glucose uptake compared to Wistar animals and the HFHS group under basal conditions. Also, the hippocampus of GK rats displayed upregulated leptin receptor, IL-1β, and IL-6 gene expression and IL-1β and the subunit of the transcription factor NF-κB (p-p65) protein expression. No significant alterations were detected in the hippocampus of HFHS rats. Our data indicated that a genetic predisposition to T2DM has significant brain deteriorating features, including brain glucose hypometabolism, neuroinflammation, and leptin signaling disruption in the hippocampal area.