Abstract 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.
The medical management of obesity has been transformed by the introduction of obesity medicines (OMs), based on the actions of glucagon-like peptide-1 and other nutrient-stimulated hormones, enabling the achievement of unprecedented weight reduction through pharmacotherapy. Here we review our current understanding of key issues surrounding obesity treatment, weight reduction, and improving health for people living with obesity. Key gaps in our knowledge of fundamental aspects of energy homeostasis are identified with a focus on their translational importance for improving outcomes. We discuss the utility of weight and health metrics, heterogeneity in achievement of clinical outcomes, individualization of treatment targets and goals, strengths and limitations of clinical trial, observational and real-world data (RWD), opportunities for improving the joint use of lifestyle management and OMs, gaps in our understanding of the long-term safety and side effects of current and emerging medicines, and the potential negative effects of losing weight. Collectively, while not intended as guidance for treatment, this document highlights the considerable progress and new research opportunities for interrogating basic and clinical science with the goal of translating advances in endocrine science into optimized outcomes for a broad range of individuals along the continuum of the weight journey.
Obesity is a growing global health challenge associated with major cardiometabolic complications. While bariatric surgery remains the most effective treatment for severe obesity, recent advances in incretin-based pharmacotherapy, multi-receptor agonists, and endoscopic bariatric procedures have substantially expanded therapeutic options. Beyond mechanical restriction, these interventions exert their effects through complex hormonal and neurophysiological mechanisms involving gut-brain signaling, gastric motility, and enteroendocrine adaptations. Gut-derived hormones, including ghrelin, glucagon-like peptide-1 (GLP-1), peptide YY (PYY), amylin, and leptin, play a central role in the regulation of hunger, satiation, and satiety by integrating nutrient sensing, vagal afferent signaling, and central hypothalamic pathways. Surgical procedures such as laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass induce profound and durable hormonal remodeling, whereas endoscopic sleeve gastroplasty primarily modulates gastric physiology with more modest and heterogeneous endocrine effects. Intragastric balloons induce a transient delay in gastric emptying and achieve moderate short-term weight loss, although their metabolic and weight-loss effects appear limited in durability. In parallel, GLP-1 receptor agonists and emerging multi-agonist therapies reproduce several post-bariatric hormonal adaptations and achieve clinically meaningful weight loss. In this review, we summarize current knowledge on digestive hormone physiology and provide an updated overview of the hormonal mechanisms underlying pharmacologic, endoscopic, and surgical bariatric interventions, highlighting their respective roles within a continuum of obesity treatment strategies.
