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Abstract
Type 2 diabetes (T2D) is a metabolic disorder characterized by insulin resistance and β-cell dysfunction, affecting over half a billion individuals worldwide, with obesity being a major risk factor. While genetic predisposition contributes to T2D, lifestyle factors such as a high-fat, high-sugar Western diet exacerbate disease progression. Emerging evidence suggests that the innate immune receptor nucleotide-binding oligomerization domain 1 (Nod1) plays a pivotal role in diet-induced insulin resistance by responding to both pathogen-associated molecular patterns (PAMPs) from gut microbiota and damage-associated molecular patterns (DAMPs) derived from dietary fats. However, whether Nod1-mediated insulin resistance is driven primarily by PAMPs or DAMPs remains unclear.
To address this, we examined the role of Nod1 in insulin resistance across different metabolic contexts. First, we assessed Nod1 knockout (KO) mice under germ-free conditions to isolate the contribution of DAMPs in diet-induced glucose intolerance. Nod1 deficiency conferred protection from high-fat, high-sucrose diet-induced insulin resistance, independent of microbiota, indicating a central role of lipid DAMPs in Nod1 activation. Second, we investigated the tissue-specific effects of Nod1 by directly infusing palmitate into whole-body and skeletal muscle-specific Nod1 KO mice. Our results demonstrated that Nod1 deletion improved insulin sensitivity, particularly in skeletal muscle, highlighting a direct role for lipid-induced Nod1 activation in peripheral glucose metabolism. Lastly, we explored the role of macrophage Nod1 in obesity-associated diabetes using myeloid-specific Nod1 KO mice. Unexpectedly, our findings revealed that the commonly used Lyz2Cre model independently influenced glucose metabolism, emphasizing the importance of including Cre-only controls in conditional knockout studies. This highlights the need for developing a more precise animal model to accurately assess the role of Nod1 in macrophages.
Together, these findings establish Nod1 as a critical mediator of fat-induced insulin resistance, independent of gut microbiota, with significant implications for metabolic disease research and potential therapeutic strategies targeting Nod1 signaling in obesity-associated diabetes.
