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en: Ghrelin Promotes Lipid Uptake into White Adipose Tissue via Endothelial Growth Hormone Secretagogue-Receptor in Mice

en: Background/Objectives: Endothelial peroxisome proliferator-activated receptor gamma (PPARγ) regulates adipose tissue by facilitating lipid uptake into white adipocytes, but the role of endothelial lipid transport in systemic energy balance remains unclear. Ghrelin conveys nutritional information through the central nervous system and increases adiposity, while deficiency in its receptor, growth hormone secretagogue-receptor (GHSR), suppresses adiposity on a high-fat diet. This study aims to examine the effect of ghrelin/GHSR signaling in the endothelium on lipid metabolism. Methods: We compared the effects of ghrelin on adiposity and lipid uptake into adipocytes in wild-type and GHSR-null mice. Transgenic mice expressing GHSR selectively in endothelial cells were also generated and compared with global GHSR-null and wild-type mice. The impact of ghrelin on lipid uptake-related genes was assessed in cultured endothelial cells. Results: Ghrelin increased adiposity and triglyceride clearance in wild-type but not in GHSR-null mice. GHSR-null mice showed higher serum triglyceride after olive oil gavage and lower white adipose tissue (WAT) weight on a high-fat diet, suggesting impaired lipid uptake. Restoring GHSR expression in endothelial cells increased lipoprotein lipase activity, lipid uptake into WAT, and WAT weight. Ghrelin enhanced free fatty acid uptake and the expression of lipid uptake genes in cultured endothelial cells, whereas these effects were absent in GHSR-null mice-derived endothelial cells. Knockdown of PPARγ revealed that ghrelin/GHSR signaling in endothelial cells promoted lipid uptake via endothelial PPARγ. Conclusions: Endothelial GHSR is key for regulating lipid metabolism via PPARγ in response to ghrelin and for the role of endothelium in regulating white adipocyte metabolism. Targeting endothelial ghrelin signaling may be a promising therapeutic approach for managing excessive adiposity and associated metabolic disorders.

en: Nutrients

ja: Nutrients


en: Deficiency Causes Mitoribosome Excess in Diabetic Nephropathy Mediated by Transcriptional Repressor HIC1.

en: overexpression preserved mitoribosomal function, suggesting its protective role in DN.

en: International Journal of Molecular Sciences


en: Ability of NAD and Sirt1 to epigenetically suppress albuminuria.

en: The time for diabetic nephropathy (DN) to progress from mild to severe is long. Thus, methods to continuously repress DN are required to exert long-lasting effects mediated through epigenetic regulation. In this study, we demonstrated the ability of nicotinamide adenine dinucleotide (NAD) and its metabolites to reduce albuminuria through Sirt1- or Nampt-dependent epigenetic regulation. We previously reported that proximal tubular Sirt1 was lowered before glomerular Sirt1. Repressed glomerular Sirt1 was found to epigenetically elevate Claudin-1. In addition, we reported that proximal tubular Nampt deficiency epigenetically augmented TIMP-1 levels in Sirt6-mediated pathways, leading to type-IV collagen deposition and diabetic fibrosis. Altogether, we propose that the Sirt1/Claudin-1 axis may be crucial in the onset of albuminuria at the early stages of DN and that the Nampt/Sirt6/TIMP-1 axis promotes diabetic fibrosis in the middle to late stages of DN. Finally, administration of NMN, an NAD precursor, epigenetically potentiates the regression of the onset of DN to maintain Sirt1 and repress Claudin-1 in podocytes, suggesting the potential use of NAD metabolites as epigenetic medications for DN.

en: Clinical and Experimental Nephrology

ja: Clinical and Experimental Nephrology


en: PCK1 Protects against Mitoribosomal Defects in Diabetic Nephropathy in Mouse Models.

en: PCK1 preserves mitoribosomal function and may play a novel protective role in DN.

en: Journal of the American Society of Nephrology


en: Pre-emptive Short-term Nicotinamide Mononucleotide Treatment in a Mouse Model of Diabetic Nephropathy.

en: The activation of NAD+-dependent deacetylase, Sirt1, by the administration of nicotinamide mononucleotide (NMN) ameliorates various aging-related diseases. Diabetic db/db mice were treated with NMN transiently for 2 weeks and observed for effects on diabetic nephropathy (DN). At 14 weeks after the treatment period, NMN attenuated the increases in urinary albumin excretion in db/db mice without ameliorating hemoglobin A1c levels. Short-term NMN treatment mitigated mesangium expansion and foot process effacement, while ameliorating decreased Sirt1 expression and increased claudin-1 expression in the kidneys of db/db mice. This treatment also improved the decrease in the expression of H3K9me2 and DNMT1. Short-term NMN treatment also increased kidney concentrations of NAD+ and the expression of Sirt1 and nicotinamide phosphoribosyltransferase (Nampt), and it maintained nicotinamide mononucleotide adenyltransferase1 (Nmnat1) expression in the kidneys. In addition, survival rates improved after NMN treatment. Short-term NMN treatment in early-stage DN has remote renal protective effects through the upregulation of Sirt1 and activation of the NAD+ salvage pathway, both of which indicate NMN legacy effects on DN.

ja: Journal of the American Society of Nephrology


en: Diabetic condition induces hypertrophy and vacuolization in glomerular parietal epithelial cells.

en: Diabetic nephropathy (DN) is accompanied by characteristic changes in the glomerulus, but little is known about the effect of diabetes on parietal epithelial cells (PECs). In this study, a descriptive analysis of PECs was undertaken in diabetic db/db mice and in diabetic patients. PEC hypertrophy was significantly more prominent in diabetic mice than in nondiabetic mice, and this was evident even at the early stage. Additionally, the number of vacuoles in PECs was markedly increased in diabetic mice, suggesting the presence of cellular injury in PECs in DN. Although rare, binuclear cells were observed in mice with early diabetes. In cultured PECs, a high glucose condition, compared with normal glucose condition, induced cellular hypertrophy and apoptosis. Flow cytometry showed that some PECs in the G0 phase reentered the cell cycle but got arrested in the S phase. Finally, in human diabetic subjects, hypertrophy and vacuolization were observed in the PECs. Our data showed that PECs undergo substantial changes in DN and may participate in rearrangement for differentiation into podocytes.

en: Scientific Reports

ja: Scientific Reports