Overweight and obesity have become global epidemics in recent decades, affecting over 2.5 billion and 890 million people, respectively, in 2022. These conditions are associated with metabolic disorders, including cardiovascular diseases, type 2 diabetes, non-alcoholic fatty liver disease (NAFL), musculoskeletal diseases, chronic kidney disease, and predisposes to an increased risk of certain cancers and autoimmune diseases. Obesity-related comorbidities contribute to 2.8 million deaths annually worldwide and have significant implications for public health and healthcare systems. As obesity and related metabolic diseases have reached epidemic proportions, understanding their causes and developing new approaches for prevention and treatment is now a top priority. However, this endeavour is made challenging by the complex aetiology of these diseases, which includes factors such as host genetics, diet, and the microbiota. The gut microbiota, predominantly composed of commensal bacteria, plays a crucial role in maintaining host health. Emerging evidence suggests that pattern recognition receptors (PRRs) involved in sensing microbiota-derived molecules also regulate obesity-related inflammation, insulin resistance, metabolic dysregulation, and barrier dysfunction. Recently, alpha kinase 1 (ALPK1) has been identified as a novel PRR sensing the small metabolite ADP-heptose produced by Gram-negative bacteria. Our research has shown that commensal bacteria can activate the ALPK1 pathway. Moreover, human genome-wide association studies (GWAS) and longitudinal genetic epidemiological studies have linked single nucleotide polymorphisms (SNPs) in the ALPK1 locus to obesity, body weight index, and type 2 diabetes. Despite advances in understanding the microbiota and PRRs in metabolic homeostasis, the role of ALPK1 in this context remains unexplored. Our preliminary unpublished data indicate a significant impact of ALPK1 deletion on weight gain, glucose response, and insulin tolerance. In light of this evidence, we hypothesize that ALPK1 is a central signaling pathway activated by microbiota-derived cues that regulate host metabolic homeostasis. The overarching objective of the Ob-ALPK1 project is to characterize how ALPK1 regulates obesity and diabetes. To achieve this, we will use transdisciplinary approaches, combining unique animal models with state-of-the-art primary murine and human cell in vitro assays, metabolic profiling, and genomic/transcriptomic analysis in humans. In this project, we will address the mechanisms and cellular targets involved in ALPK1-dependent modulation of weight gain, glycemia, and metabolic dysregulation. We will also assess the clinical relevance of our findings in humans and explore the therapeutic potential of the ALPK1 pathway in vivo. Overall, this innovative project aims to uncover new mechanisms and bioactive molecular signals from the microbiota that can be targeted to prevent and treat obesity and metabolic syndromes.