論文

Sodium-glucose co-transporter 2 (SGLT2) inhibitors promote weight loss in patients with type 2 diabetes mellitus; however, the underlying mechanisms remain unknown. This study investigated the role of renal autonomic nerves in SGLT2 inhibitor-induced lipolysis and body weight reduction by utilizing the renal denervation technique. The results indicated that renal autonomic nerves mediated lipolysis in mice fed a high-fat diet following treatment with tofogliflozin, an SGLT2 inhibitor. The effect was attenuated by renal denervation or β3-adrenergic blockade. Metabolomic analysis revealed that treatment with tofogliflozin elevated renal adenosine, which in turn activated adipose sympathetic nerves, as evidenced by increased norepinephrine concentrations in adipose tissue, thereby promoting lipolysis. These findings uncover a novel reno-adipose neurocircuitry linking renal energy depletion to systemic fatty acid oxidation, providing insights into the sustained weight-reducing effects of SGLT2 inhibitors. (Figure presented.)

Rationale : The (pro)renin receptor [(P)RR], encoded in ATP6AP2 , plays a key role in the activation of local renin-angiotensin system (RAS). A truncated form of (P)RR, termed M8.9, was also found to be associated with the vacuolar H + -ATPase (V-ATPase), implicating a non–RAS-related function of ATP6AP2. Objective : We investigated the role of (P)RR/ATP6AP2 in murine cardiomyocytes. Methods and Results : Cardiomyocyte-specific ablation of Atp6ap2 resulted in lethal heart failure; the cardiomyocytes contained RAB7- and lysosomal-associated membrane protein 2 (LAMP2)-positive multivesicular vacuoles, especially in the perinuclear regions. The myofibrils and mitochondria remained at the cell periphery. Cardiomyocyte death was accompanied by numerous autophagic vacuoles that contained undigested cellular constituents, as a result of impaired autophagic degradation. Notably, ablation of Atp6ap2 selectively suppressed expression of the V O subunits of V-ATPase, resulting in deacidification of the intracellular vesicles. Furthermore, the inhibition of intracellular acidification by treatment with bafilomycin A1 or chloroquine reproduced the phenotype observed for the (P)RR/ATP6AP2-deficient cardiomyocytes. Conclusions : Genetic ablation of Atp6ap2 created a loss-of-function model for V-ATPase. The gene product of ATP6AP2 is considered to act as in 2 ways: (1) as (P)RR, exerting a RAS-related function; and (2) as the V-ATPase-associated protein, exerting a non–RAS-related function that is essential for cell survival.

Distinct metabolic conditions rewire circadian-clock-controlled signaling pathways leading to the de novo construction of signal transduction networks. However, it remains unclear whether metabolic hallmarks unique to pluripotent stem cells (PSCs) are connected to clock functions. Reprogramming somatic cells to a pluripotent state, here we highlighted non-canonical functions of the circadian repressor CRY1 specific to PSCs. Metabolic reprogramming, including AMPK inactivation and SREBP1 activation, was coupled with the accumulation of CRY1 in PSCs. Functional assays verified that CRY1 is required for the maintenance of self-renewal capacity, colony organization, and metabolic signatures. Genome-wide occupancy of CRY1 identified CRY1-regulatory genes enriched in development and differentiation in PSCs, albeit not somatic cells. Last, cells lacking CRY1 exhibit differential gene expression profiles during induced PSC (iPSC) reprogramming, resulting in impaired iPSC reprogramming efficiency. Collectively, these results suggest the functional implication of CRY1 in pluripotent reprogramming and ontogenesis, thereby dictating PSC identity.

The ATPase 6 accessory protein 2 (ATP6AP2)/(pro)renin receptor (PRR) is essential for the biogenesis of active vacuolar H(+)-ATPase (V-ATPase). Genetic deletion of ATP6AP2/PRR causes V-ATPase dysfunction and compromises vesicular acidification. Here, we characterized the domains of ATP6AP2/PRR involved in active V-ATPase biogenesis. Three forms of ATP6AP2/PRR were found intracellularly: full-length protein and the N- and C-terminal fragments of furin cleavage products, with the N-terminal fragment secreted extracellularly. Genetic deletion of ATP6AP2/PRR did not affect the protein stability of V-ATPase subunits. The extracellular domain (ECD) and transmembrane domain (TM) of ATP6AP2/PRR were indispensable for the biogenesis of active V-ATPase. A deletion mutant of ATP6AP2/PRR, which lacks exon 4-encoded amino acids inside the ECD (Δ4M) and causes X-linked mental retardation Hedera type (MRXSH) and X-linked parkinsonism with spasticity (XPDS) in humans, was defective as a V-ATPase-associated protein. Prorenin had no effect on the biogenesis of active V-ATPase. The cleavage of ATP6AP2/PRR by furin seemed also dispensable for the biogenesis of active V-ATPase. We conclude that the N-terminal ECD of ATP6AP2/PRR, which is also involved in binding to prorenin or renin, is required for the biogenesis of active V-ATPase. The V-ATPase assembly occurs prior to its delivery to the trans-Golgi network and hence shedding of ATP6AP2/PRR would not affect the biogenesis of active V-ATPase.

Aging is associated with metabolic dysfunction and cardiovascular abnormalities. Defective nicotinamide adenine dinucleotide (NAD+) biosynthesis correlates with aging and aging-associated complications. However, the precise molecular mechanisms linking aging-associated NAD+ deficiency to cardiometabolic dysfunction remain unclear. Herein, we examined whether nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD+ biosynthesis, influences vascular endothelial function and whole-body metabolic and hemodynamic homeostasis during aging. Vascular endothelial cell–specific Nampt knockout (VeNKO) mice fed a regular chow diet exhibited no cardiometabolic abnormalities, whereas male VeNKO mice fed a high-fat diet exhibited reduced angiogenesis, resulting in impaired subcutaneous adipogenesis, impaired glucose metabolism, and hemodynamic disturbances. Mechanistically, NAMPT loss attenuated NAD+-dependent deacetylase sirtuin-1 (SIRT1) and endothelial nitric oxide synthase (eNOS) signaling, impairing angiogenesis. Aged mice exhibited endothelial NAD+ depletion driven by an imbalance between NAMPT-mediated NAD+ biosynthesis and consumption, leading to impaired eNOS signaling and associated angiogenic and cardiometabolic dysfunction, similar to that observed in VeNKO mice. Nicotinamide mononucleotide administration replenished vascular endothelial NAD+ levels, improved angiogenesis, restored subcutaneous adipose tissue volume, and ameliorated aging-associated cardiometabolic dysfunction. Collectively, our findings provide mechanistic and therapeutic insights into vascular endothelial NAMPT–NAD+–SIRT1–eNOS signaling related to aging-associated cardiometabolic disorders.

昼夜の明暗周期に同期しながらも,自律的で固有の約24時間周期のリズムを生体は有しており,概日リズムと呼ばれる。概日リズムは生体時計を中心とする転写翻訳フィードバック機構を基軸に,代謝恒常性を維持している。近年の研究から,夜勤や深夜の食事が概日リズムの乱れを通じて,肥満の原因となることが明らかになってきた。これまで肥満に関わる知見の多くが,カロリー摂取量やエネルギー消費量に焦点が当てられてきたが,食事摂取や空腹のタイミングが重要な役割を果たすことが分かってきている。本項では,概日リズムの同調因子としての食事のタイミングと内分泌代謝リズムの肥満の病態への関与を概説する。(著者抄録)

概日リズムは生体が昼夜の変化する環境に予測して適応する内分泌代謝恒常性に重要な機構である。その中心的な役割を生体時計が担っており、地球の自転に伴う太陽光の明暗による調節を受けながら、約24時間周期の行動、代謝、ホルモンなどのリズムを生み出している。哺乳類の末梢組織に存在する生体時計は食事や運動にも同調する一方で、食事や運動に対する昼夜の代謝応答を制御することも分かっている。近年の研究で組織や細胞間での時計の連携や協調が、個体のエネルギー代謝恒常性に重要であることも明らかになりつつある。(著者抄録)

インスリン発見以前,糖質制限食は唯一の糖尿病治療法であった.インスリン療法の普及とともに20世紀では民間療法として扱われていたが,21世紀になり,血糖改善に最善の食事法とされるに至っている.1型糖尿病,2型糖尿病を問わず,HbA1c改善や低血糖頻度減少や薬剤費軽減を期待可能な食事法であり,わが国でのさらなる普及が期待されている.一方で,時間制限食は概日時計や栄養センシング分子の活性化を介して,体重減少や耐糖能改善,血圧低下などの心血管内分泌代謝の改善効果が示されており,糖尿病,高血圧,メタボリック症候群などの生活習慣病に対する新たな食事法として注目されている.本稿では,糖質制限や時間制限食のエビデンスと可能性を概説する.(著者抄録)

＜文献概要＞処方のポイント　●原発性アルドステロン症のスクリーニングや確定診断のための検査の際には,可能な限りレニン・アンジオテンシン系に影響がない薬剤を選択する.また,低カリウム血症を合併する症例では,カリウム製剤による血清カリウム値の補正を十分に行ったうえで検査を実施する.●原発性アルドステロン症の確定診断に至った高血圧の症例では,禁忌がない限りミネラルコルチコイド受容体拮抗薬(MRB)を第一選択とする.