TNF-ALPHA AS A CENTRAL METABOLIC AND REWARD FUNCTION MEDIATOR IN RODENT MODEL OF OBESITY INDUCED BY HIGH-FAT HIGH-SUGAR DIETS

Obesity is a growing global health concern partly driven by high-fat, high-sugar (HFHS) diets. Beyond peripheral metabolic dysfunction, HFHS diets disrupt central reward circuits regulating food preference and motivated feeding, by promoting neuroinflammation and triggering a shift from homeostatic to hedonic control. However, the mechanisms linking diet-induced inflammation to reward-circuit dysfunction remain poorly understood. Here we focus on tumor necrosis factor-α (TNF-α), a pro-inflammatory cytokine that also functions as an adipokine, and is produced by both adipose tissue peripherally and glial cells centrally. Further, TNF-α can mediate a homeostatic form of synaptic plasticity, and negatively regulate changes in reward function driven by addictive substances.
We tested TNF-α’s contribution in mice fed with HFHS diets. WT, TNF-α knockout (TNFKO) mice were maintained on HFHS for 9-10 weeks. Behavioral assays assessed anxiety and memory capacity, while synaptic function was examined by mEPSC recordings. HFHS feeding in WT mice produced a circuit-specific synaptic dissociation, characterized by increased excitatory synaptic strength in ventral hippocampus and reduced excitatory strength in striatum, accompanied by elevated anxiety-like behavior and impaired memory. Notably, these changes didn't occur in TNFKO. However, TNFKO mice exhibited exaggerated weight gain despite preserved behavior, indicating that TNF-α restrains weight gain while driving maladaptive synaptic plasticity and behaviours. Thus, these findings identify TNF-α as a critical regulator that dissociates metabolic outcomes from reward-related neural adaptations during HFHS exposure. Understanding how TNF-α contributes to diet-induced changes will reveal novel mechanisms linking obesity to altered brain reward circuitry, identify potential therapeutic targets for diet-induced obesity.