Weight loss with glucagon-like peptide-1 receptor agonists (GLP-1RAs) is heterogeneous across individuals, yet the genetic causes of this variation are not fully known. We integrated exome sequencing data with electronic health records within the Helix Research Network (n = 351,818). Here, we show that, among 13,725 GLP-1RA-treated adults, carriers of rare damaging GLP1R variants lose less weight with semaglutide than matched non-carriers but achieve a near-normal tirzepatide response. Carriers of rare variants in GIPR, which encodes the glucose-dependent insulinotropic polypeptide receptor, the second target of tirzepatide, also achieve normal weight loss responses. Our study demonstrates that rare GLP1R variants affect the response to semaglutide but not to tirzepatide. Rare GLP1R variants are shown to reduce weight loss with semaglutide but not tirzepatide, suggesting GLP1R genetic variation as a pharmacogenetic determinant of GLP-1 receptor agonist efficacy.
Excess cholesterol accumulates in colorectal cancer (CRC) and promotes its progression, yet systemic cholesterol-lowering has limited benefits and safety concerns. Here we show that redirecting intestinal cholesterol metabolism through the gut microbiota generates a metabolite, 4-cholesten-3-one (4-C-3), which suppresses CRC growth. A screen of microbial cholesterol metabolites showed that 4-C-3 is depleted in faecal and tumour samples from patients with CRC. 4-C-3 suppresses tumour growth in CRC cell lines, patient-derived organoids and xenografts. Mechanistically, 4-C-3 suppresses two major oncogenic drivers of CRC by inhibiting epidermal growth-factor receptor activation and stabilizing mutant oncogenic KRAS in an inactive state, thereby overcoming KRAS-driven resistance to anti-epidermal growth-factor receptor therapy. As proof of concept, restoring 4-C-3 using either Oscillibacter ruminantium, a natural 4-C-3 producer reduced in CRC, or a non-pathogenic Escherichia coli engineered to convert intestinal cholesterol into 4-C-3, lowered intratumoral cholesterol and induced tumour regression in preclinical models without overt toxicity. These findings uncover a microbiota–cholesterol metabolic pathway that can be harnessed through microbiome engineering to selectively target CRC and overcome therapy resistance. Modulation of intratumoral cholesterol metabolism through delivery of a microbiota-derived metabolite is shown to induce colorectal cancer regression in mice.
Endotrophin (ETP), a C-terminal cleavage fragment of the collagen VI α3 chain, has emerged as a key mediator of fibroinflammation and a clinically relevant biomarker of disease progression. Accumulating evidence from both preclinical models and human studies implicates elevated ETP levels as a driver of tissue remodelling, metabolic dysfunction, inflammation and fibrosis across multiple organ systems. Increased ETP has been linked to obesity-associated adipose tissue dysfunction, steatotic liver disease, breast cancer progression, chronic kidney disease and cardiovascular disease, underscoring its broad pathological relevance. The convergence of mechanistic and clinical data positions ETP as a promising therapeutic target across a range of diseases linked by common ETP-driven dysfunction. Here we synthesize current knowledge of ETP’s regulation and functions, critically evaluate its role in diverse disease contexts and outline key unanswered questions and emerging strategies for therapeutic intervention. Maya-Ramos, Funcke and Scherer provide a concise overview of the collagen cleavage fragment endotrophin, a mediator of fibroinflammation and a biomarker of progression of various cardiometabolic diseases.
Sympathetic neurons stimulate adipose thermogenic recruitment, which is further sustained by extracellular matrix (ECM) remodelling; however, the direct link between sympathetic neurons and ECM remodelling is still missing. Here we show the presence of a subpopulation of β-glucuronidase (GUSB)-enriched sympathetic neurons that drive ECM reorganization essential for thermogenic programming in male mice. We demonstrate that cold exposure triggers these neurons to secrete GUSB, an ECM degradation enzyme that processes glycosaminoglycans into bioactive chondroitin sulphate (CS) fragments within the adipose tissue microenvironment. The generated CS acts through CD97 receptors on adipocytes to potentiate thermogenic activation. Importantly, we identify human GUSB variants leading to the defect of this mechanism, linking this sympathetic-ECM crosstalk to obesity. Furthermore, CS supplementation ameliorates diet-induced obesity by enhancing thermogenic recruitment in murine models. Thus, our findings uncover an ECM-remodelling group of sympathetic neurons important for thermogenic regulation and could serve as a potential strategy against obesity. A subpopulation of β-glucuronidase-enriched sympathetic neurons regulates thermogenesis in male mice, via extracellular matrix remodelling.
The cellular microenvironment surrounding sympathetic nerves is emerging as an important regulator of adipose tissue metabolism. A new study published in Nature Metabolism shows that a discrete population of GUSB-expressing sympathetic neurons can modulate adipose thermogenesis by remodelling the extracellular matrix.
