👤 Andrew Vick

Functional co- and tri-agonists at the receptors for GLP-1, GIP and glucagon effectively decrease body weight and hyperglycemia but are associated with adverse gastrointestinal effects related to GLP-1R agonism. Here we report the discovery that obesity can be reversed in the absence of a functional GLP-1R. It propelled the identification of a unimolecular GIPR:GCGR co-agonist lacking GLP-1 activity that corrects obesity in obese mice and rats. Selective, dual, and triple sustained-action agonists at GIPR, GCGR and GLP-1R were used to assess body weight and glucose management in diet-induced obese (DIO) wildtype (WT) and GLP-1R knock-out (KO) mice. Indirect calorimetry and pair-feeding studies were used to characterize the magnitude of weight lowering specifically to suppression of food intake relative to energy expenditure. When used in physical co-mixture, selective GIPR agonism interacts with selective GCGR agonism to correct obesity and enhance glycemia in DIO mice. Retatrutide a balanced GLP-1R:GIPR:GCGR triagonist normalized body weight in obese GLP-1R KO mice. BWB3054, a fatty acylated GIPR:GCGR co-agonist, was identified as comparably potent as retatrutide to induce cAMP production at the mGIPR, and 4-fold reduced at mGCGR, but notably more than 100-fold diminished at mGLP-1R. Despite minimal relative GLP-1R potency, BWB3054 reduces excess body weight in obese DIO-mice to a similar degree as that observed for retatrutide in obese GLP-1R KO mice. Correction of obesity and glycemia in mice without employing GLP-1 agonism was demonstrated by three independent methods (GLP-1R KO with retatrutide, GIPR:GCGR physical co-agonism mixture, and GIPR:GCGR covalent co-agonist) which advocate for the prospect that the adverse GI effects commonly associated with its use might be avoided. Show less

Abnormal metabolism is a fundamental hallmark of cancer and represents a therapeutic opportunity, yet its regulation by oncogenes remains poorly understood. Here, we uncover that JMJD1C, a jumonji C (JmjC)-containing H3K9 demethylase, is a critical regulator of aberrant metabolic processes in homeobox A9 (HOXA9)-dependent acute myeloid leukemia (AML). JMJD1C overexpression increases in vivo cell proliferation and tumorigenicity through demethylase-independent upregulation of a glycolytic and oxidative program, which sustains leukemic cell bioenergetics and contributes to an aggressive AML phenotype in vivo. Targeting JMJD1C-mediated metabolism via pharmacologic inhibition of glycolysis and oxidative phosphorylation led to ATP depletion, induced necrosis/apoptosis and decreased tumor growth in vivo in leukemias co-expressing JMJD1C and HOXA9. The anti-metabolic therapy effectively diminished AML stem/progenitor cells and reduced tumor burden in a primary AML patient-derived xenograft. Our data establish a direct link between drug responses and endogenous expression of JMJD1C and HOXA9 in human AML cell line- and patient-derived xenografts. These findings demonstrate a previously unappreciated role for JMJD1C in counteracting adverse metabolic changes and retaining the metabolic integrity during tumorigenesis, which can be exploited therapeutically. Show less

Cellular proteins are degraded in either proteasomes or lysosomes depending on the types of ubiquitin chains that covalently modify them. It is not known whether the choice between these two pathways is physiologically regulated. The Lys48-polyubiquitin chain is the major signal directing proteins for degradation in proteasomes. Here, we report the unexpected finding that canonical Wnt signaling translocates some K48-linked polyubiquitinated proteins to the endolysosomal pathway. Proteasomal target proteins, such as b-catenin, Smad1, and Smad4, were targeted into endolysosomes in a process dependent on GSK3 activity. Relocalization was also dependent on Axin1 and the multivesicular body (MVB) proteins HRS/Vps27 and Vps4. The Wnt-induced accumulation of K48-linked polyubiquitinated proteins in endolysosomal organelles was accompanied by a transient decrease in cellular levels of free mono-ubiquitin, which may contribute to Wnt-regulated stabilization of proteins (Wnt/ STOP). We conclude that Wnt redirects Lys48-polyubiquitinated proteins that are normally degraded in proteasomes to endolysosomes. Show less