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Lipids are the most energy‐dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron‐mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high‐fat diet‐induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity. Synopsis: We show that upon fat ingestion, Protein Kinase D2 stimulates chylomicron‐mediated triglyceride absorption in the intestine. Targeting PKD2, genetically or with small molecule inhibitors, reduces triglycerides absorption and prevents the development of obesity in mice and presumably in humans. PKD2 enhances chylomicron size and therefore chylomicron‐mediated triglycerides absorption.PKD2 phosphorylates chylomicron‐associated lipoprotein, APOA4.Inhibition of PKD2 diminishes obesity and associated diabetes.PKD2 activity correlates with triglycerides levels in obese patients. [ABSTRACT FROM AUTHOR]

C─H⋯O hydrogen bonds constitute a unique class of cohesive interactions. Their properties are similar to those of canonical H‐bonds, although their energy is significantly lower, typically in the 0.5–2.5 kcal/mol range. Polarised C─H groups, such as those adjacent to electronegative groups, or within aromatic moieties, are particularly strong donors. C─H⋯O bonds are ubiquitous in nucleic acids and in proteins, notably stabilizing the β‐sheet secondary structure. They have also been observed in numerous protein‐ligand interactions. Here, we analysed crystal structures, deposited in the Protein Data Bank, of complexes of FDA‐approved protein kinase inhibitors with cognate kinases, to assess the possible role of C─Hinhibitor⋯Oprotein hydrogen bonds. The conserved hinge motif of protein kinases with two solvent‐exposed carbonyl groups and one exposed backbone amide, is well known to be involved in canonical H‐bonding with inhibitors. We now find that in virtually all complexes where the inhibitor interacts with the hinge backbone, at least one of the hinge carbonyl groups accepts an H‐bond from a C─H inhibitor group, which is either aromatic or adjacent to an electronegative group. These observations are important for design of hinge‐binding scaffolds of novel kinase inhibitors for therapeutic use. [ABSTRACT FROM AUTHOR]