The Microbiome-Metabolokine-Adipokine Axis in Insulin Resistance: Adaptive and Maladaptive FGF21-GDF15 Signaling.

Insulin resistance emerges from disturbances in interorgan metabolic communication in which nutrient exposure, microbial metabolism, and host endocrine responses interact across multiple metabolic compartments. This state-of-the-art review proposes a revised Microbiome-Metabolokine-Adipokine (MMA) Axis as a focused framework linking gut microbial metabolic signals with enteroendocrine, hepatic, and adipose responses and the stress-responsive metabolokines fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). Microbiome-derived and microbiome-modified signals, including short-chain fatty acids, bile acids, branched-chain amino acid-related metabolites, tryptophan-derived metabolites, and microbial inflammatory products, can influence intestinal receptor signaling, incretin secretion, hepatic nutrient sensing, adipose lipid buffering, and systemic insulin sensitivity. Within this network, FGF21 and GDF15 are positioned as distinct but complementary adaptive endocrine signals rather than components of a fixed sequential pathway: FGF21 predominantly coordinates responses to nutrient and metabolic stress, whereas GDF15 communicates broader cellular stress through GFRAL-RET-dependent regulation of nutrient intake and energy balance. Importantly, persistent elevation of either metabolokine during insulin-resistant states should not automatically be interpreted as endocrine resistance or maladaptation. We instead propose that progression toward insulin resistance reflects a context-dependent mismatch between increasing metabolic stress and the capacity of integrated endocrine responses to maintain metabolic flexibility and substrate homeostasis. Current evidence strongly supports individual microbiome-metabolite, enteroendocrine, hepatic, adipose, FGF21, and GDF15 signaling modules, but a direct causal microbiome-FGF21-GDF15 sequence has not been established in humans. The revised MMA Axis therefore provides a testable framework for defining how microbiome-derived metabolic signals interface with host endocrine adaptation during the development of insulin resistance.