Saturated Fatty Acids Produce an Inflammatory Response Predominantly through the Activation of TLR4 Signaling in Hypothalamus: Implications for the Pathogenesis of Obesity

TLDR

In diet‑induced obesity, hypothalamic inflammation drives resistance to insulin and leptin, yet the specific dietary fat‑initiated events that trigger cytokine expression remain unclear. We investigated whether dietary fats activate toll‑like receptors 2/4 and endoplasmic reticulum stress to induce hypothalamic cytokine expression in rodents. Long‑chain saturated fatty acids predominantly stimulate TLR4 signaling, inducing cytokine production and ER stress, whereas monounsaturated fats do not elicit leptin resistance; TLR4 loss or inhibition protects mice from diet‑induced obesity, establishing TLR4 as the key mediator of saturated‑fat‑induced hypothalamic inflammation and anorexigenic resistance.

Abstract

In animal models of diet-induced obesity, the activation of an inflammatory response in the hypothalamus produces molecular and functional resistance to the anorexigenic hormones insulin and leptin. The primary events triggered by dietary fats that ultimately lead to hypothalamic cytokine expression and inflammatory signaling are unknown. Here, we test the hypothesis that dietary fats act through the activation of toll-like receptors 2/4 and endoplasmic reticulum stress to induce cytokine expression in the hypothalamus of rodents. According to our results, long-chain saturated fatty acids activate predominantly toll-like receptor 4 signaling, which determines not only the induction of local cytokine expression but also promotes endoplasmic reticulum stress. Rats fed on a monounsaturated fat-rich diet do not develop hypothalamic leptin resistance, whereas toll-like receptor 4 loss-of-function mutation and immunopharmacological inhibition of toll-like receptor 4 protects mice from diet-induced obesity. Thus, toll-like receptor 4 acts as a predominant molecular target for saturated fatty acids in the hypothalamus, triggering the intracellular signaling network that induces an inflammatory response, and determines the resistance to anorexigenic signals.