Objective: Nobiletin is a dietary flavonoid that improves insulin resistance and atherosclerosis in mice with metabolic dysfunction. Dysregulation of intestinal lipoprotein metabolism contributes to atherogenesis. The objective of the study was to determine if nobiletin targets the intestine to improve metabolic dysregulation in both male and female mice. Approach and Results: Triglyceride-rich lipoprotein (TRL) secretion, intracellular triglyceride kinetics, and intestinal morphology were determined in male and female LDL (low-density lipoprotein) receptor knockout, and male wild-type mice fed a standard laboratory diet or high-fat, high-cholesterol diet ± nobiletin using an olive oil gavage, radiotracers, and electron microscopy. Nobiletin attenuated postprandial TRL levels in plasma and enhanced TRL clearance. Nobiletin reduced fasting jejunal triglyceride accumulation through accelerated TRL secretion and lower jejunal fatty acid synthesis with no impact on fatty acid oxidation. Fasting-refeeding experiments revealed that nobiletin led to higher levels of phosphorylated AKT and FoxO1 (forkhead box O1) and normal Srebf1-c expression indicating increased insulin sensitivity. Intestinal length and weight were diminished by high-fat feeding and restored by nobiletin. Both fasting and postprandial plasma GLP-1 (glucagon-like peptide-1; and likely GLP-2) were elevated in response to nobiletin. Treatment with a GLP-2 receptor antagonist, GLP-2(3-33), reduced villus length in high fat-fed mice but did not impact TRL secretion in any diet group. In contrast to males, nobiletin did not improve postprandial lipid parameters in female mice. Conclusions: Nobiletin opposed the effects of the high-fat diet by normalizing intestinal de novo lipogenesis through improved insulin sensitivity. Nobiletin prevents postprandial lipemia because the enhanced TRL clearance more than compensates for increased TRL secretion.

Postprandial triglycerides (TGs) are elevated in people with type 2 diabetes (T2D). Glucose-lowering agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, also reduce postprandial TG excursion. Although the glucose-lowering mechanisms of DPP-4 have been extensively studied, how the reduction of DPP-4 activity improves lipid tolerance remains unclear. Here, we demonstrate that gut-selective and systemic inhibition of DPP-4 activity reduces postprandial TG excursion in young mice. Genetic inactivation of Dpp4 simultaneously within endothelial cells and hematopoietic cells using Tie2 -Cre reduced intestinal lipoprotein secretion under regular chow diet conditions. Bone marrow transplantation revealed a key role for hematopoietic cells in modulation of lipid responses arising from genetic reduction of DPP-4 activity. Unexpectedly, deletion of Dpp4 in enterocytes increased TG excursion in high-fat diet–fed (HFD-fed) mice. Moreover, chemical reduction of DPP-4 activity and increased levels of GLP-1 were uncoupled from TG excursion in older or HFD-fed mice, yet lipid tolerance remained improved in older Dpp4 –/– and Dpp4 EC–/– mice. Taken together, this study defines roles for specific DPP-4 compartments, age, and diet as modifiers of DPP-4 activity linked to control of gut lipid metabolism.

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Enteroendocrine cells directly integrate signals of nutrient content within the gut lumen with distant hormonal responses and nutrient disposal via the production and secretion of peptides, including glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2). Given their direct and indirect control of post-prandial nutrient uptake and demonstrated translational relevance for the treatment of type 2 diabetes, malabsorption and cardiometabolic disease, there is significant interest in the locally engaged circuits mediating these metabolic effects. Although several specific populations of cells in the intestine have been identified to express endocrine receptors, including intraepithelial lymphocytes (IELs) and αβ and γδ T-cells (Glp1r+) and smooth muscle cells (Glp2r+), the definitive cellular localization and co-expression, particularly in regards to the Gipr remain elusive. Here we review the current state of the literature and evaluate the identity of Glp1r, Glp2r, and Gipr expressing cells within preclinical and clinical models. Further elaboration of our understanding of the initiating G-protein coupled receptor (GPCR) circuits engaged locally within the intestine and how they become altered with high-fat diet feeding can offer insight into the dysregulation observed in obesity and diabetes.

Elevated circulating dipeptidyl-peptidase 4 (DPP4) is a biomarker for liver disease, but its involvement in gluconeogenesis and metabolic associated fatty liver disease (MAFLD) progression remains unclear. Here we identified that DPP4 in hepatocytes but not Tie2 + endothelial cells regulates the local bioactivity of incretin hormones and gluconeogenesis.However, the complete absence of DPP4 (Dpp4 -/-) in aged mice with metabolic syndrome accelerates liver fibrosis without altering dyslipidemia and steatosis. Analysis of transcripts from the livers of Dpp4 -/mice displayed enrichment for inflammasome, p53, and senescence programs compared to littermate controls. High-fat high-cholesterol (HFHC)-feeding decreased Dpp4 expression in F4/80+ cells, with only minor changes in immune signaling. Moreover, in a lean mouse model of severe non-alcoholic fatty liver disease (NAFLD), phosphatidylethanolamine N-methyltransferase (Pemt -/-) mice, we observed a 4-fold increase in circulating DPP4, disassociating its release from obesity. Lastly, we evaluated DPP4 levels in patients with hepatitis C infection with dysglycemia (HOMA-IR >2) who underwent direct antiviral treatment (ribavirin). DPP4 protein levels decreased with viral clearance, and DPP4 activity levels were reduced at longer-term follow-up in ribavirin-treated patients, although metabolic factors did not improve. These data suggest elevations in DPP4 during HCV infection are not primarily regulated by metabolic disturbances.