Nicotinamide adenine dinucleotide (NAD) is an important coenzyme that participates in various energy metabolism pathways, including glycolysis, β-oxidation, and oxidative phosphorylation. Besides, it ...is a required cofactor for post-translational modifications such as ADP-ribosylation and deacetylation by poly (ADP-ribose) polymerases (PARPs) and sirtuins, respectively. Thus, NAD regulates energy metabolism, DNA damage repair, gene expression, and stress response through these enzymes. Numerous studies have shown that NAD levels decrease with aging and under disturbed nutrient conditions, such as obesity. Additionally, a decline in NAD levels is closely related to the development of various metabolic disorders, including diabetes and fatty liver disease. In addition, many studies have revealed that administration of NAD precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR), efficiently increase NAD levels in various tissues and prevent such metabolic diseases. These NAD precursors are contained in natural foods, such as cow milk, vegetables, and meats. Therefore, altered NAD metabolism can be a practical target for nutritional intervention. Recently, several human clinical trials using NAD precursors have been conducted to investigate the safety, pharmacokinetics, and efficacy against metabolic disorders such as glucose intolerance. In this review, we summarize current knowledge on the implications of NAD metabolism in metabolic diseases and discuss the outcomes of recent human clinical trials.
The human body is inhabited by numerous bacteria, fungi, and viruses, and each part has a unique microbial community structure. The gastrointestinal tract harbors approximately 100 trillion strains ...comprising more than 1000 bacterial species that maintain symbiotic relationships with the host. The gut microbiota consists mainly of the phyla Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. Of these, Firmicutes and Bacteroidetes constitute 70-90% of the total abundance. Gut microbiota utilize nutrients ingested by the host, interact with other bacterial species, and help maintain healthy homeostasis in the host. In recent years, it has become increasingly clear that a breakdown of the microbial structure and its functions, known as dysbiosis, is associated with the development of allergies, autoimmune diseases, cancers, and arteriosclerosis, among others. Metabolic diseases, such as obesity and diabetes, also have a causal relationship with dysbiosis. The present review provides a brief overview of the general roles of the gut microbiota and their relationship with metabolic disorders.
Astaxanthin is a member of the carotenoid family that is found abundantly in marine organisms, and has been gaining attention in recent years due to its varied biological/physiological activities. It ...has been reported that astaxanthin functions both as a pigment, and as an antioxidant with superior free radical quenching capacity. We recently reported that astaxanthin modulated mitochondrial functions by a novel mechanism independent of its antioxidant function. In this paper, we review astaxanthin's well-known antioxidant activity, and expand on astaxanthin's lesser-known molecular targets, and its role in mitochondrial energy metabolism.
Obesity increases the risk of cancer. Increased levels of hormones (such as oestrogen, insulin, insulin-like growth factor, and leptin), free fatty acid-induced production of reactive oxygen species, ...an altered intestinal microbiome and chronic inflammation are known to be associated with an increased cancer risk in obese subjects. However, the mechanism underlying the connection between obesity and cancer development remains elusive. Here, we show that a high-fat diet (HFD) promotes tumour initiation/progression and induces a phenotypic switch from PD-1
CD8
non-exhausted T cells to PD-1
CD8
exhausted T cells in a murine breast cancer model. While PD-1
CD8
non-exhausted T cells predominated in the mammary glands of normal diet (ND)-fed mice, PD-1
CD8
exhausted T cells accumulated in the developing tumours of HFD-fed mice. Gene expression profiles indicated that PD-1
CD8
T cells expressed higher levels of the tumour-trophic gene Opn and lower levels of the cytotoxic genes Ifng and Gzmb than did PD-1
CD8
T cells. Our study provides a possible mechanistic linkage between obesity and cancer.
Adipose tissue (AT) is composed not only of adipocytes, but also of macrophages, endothelial cells and preadipocytes. Macrophages are an important component of AT, and are involved in tissue ...homeostasis, tissue repair and fibrosis. AT‐resident macrophages are categorized into two subtypes, the M1‐like and M2‐like macrophages. M2‐like macrophages are reported to play anti‐inflammatory roles, and to be involved in clearing and removal of dying/dead adipocytes, and recruiting adipocyte progenitors (APs). M2‐like macrophages are also reported to be involved in the promotion of fibrosis in a transforming growth factor‐β‐dependent manner. However, the precise roles of M2‐like macrophages in the AT have not yet been clearly delineated. Recently, we generated genetically engineered transgenic mice in which CD206+ M2‐like macrophages can be conditionally depleted. Unexpectedly, we found that the depletion of CD206+ M2‐like macrophages resulted in the enhanced generation of smaller adipocytes, improved insulin sensitivity and proliferation of APs. We further clarified that the CD206+ M2‐like macrophages directly interact with the APs to regulate their growth/differentiation and adipogenesis, thereby controlling adiposity and systemic insulin sensitivity. In the present review, we discuss how CD206+ M2‐like macrophages provide a niche for APs and maintain glucose homeostasis.
CD206+ M2‐like macrophages play pivotal roles in white adipose tissue remodeling by serving as a niche for adipocyte progenitors (APs), inhibiting proliferation of APs and differentiation of APs into adipocytes through transforming growth factor‐β signaling.
This subgroup analysis of STELLA-LONG TERM, an ongoing 3-year post-marketing surveillance study on the long-term efficacy and safety of ipragliflozin, assessed the effect of ipragliflozin on liver ...function in type 2 diabetes mellitus (T2DM) patients. Patients were divided according to baseline liver function (normal male: ALT ≤30, female: ALT ≤20, abnormal male: ALT ≥31, female: ALT ≥21). We evaluated changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (γ-GTP), alkaline phosphatase (ALP), and fatty liver index (FLI) at 3 months of treatment; the proportion of patients with abnormal liver function whose liver function normalized after 3 months of treatment; and correlations between changes in ALT levels and efficacy variables/laboratory values. Liver function was normal in 2,570 and abnormal in 3,239 patients. Only patients with abnormal liver function showed a statistically/clinically significant decrease in AST, ALT, γ-GTP, and ALP levels at 3 months (all p < 0.05 vs. baseline). The FLI significantly decreased from 63.2677 ± 26.4363 (baseline) to 56.7137 ± 27.6484 (3 months) (p < 0.05) in the overall patient population. Liver function normalized in 20.5% (543/2,648) of patients with abnormal liver function. There was no obvious correlation between changes in ALT and changes in efficacy/laboratory parameters. Liver function improved after 3-month treatment with ipragliflozin in T2DM patients with abnormal liver function.
Dynamic metabolic changes occur in the liver during the transition between fasting and feeding. Here we show that transient ER stress responses in the liver following feeding terminated by Sdf2l1 are ...essential for normal glucose and lipid homeostasis. Sdf2l1 regulates ERAD through interaction with a trafficking protein, TMED10. Suppression of Sdf2l1 expression in the liver results in insulin resistance and increases triglyceride content with sustained ER stress. In obese and diabetic mice, Sdf2l1 is downregulated due to decreased levels of nuclear XBP-1s, whereas restoration of Sdf2l1 expression ameliorates glucose intolerance and fatty liver with decreased ER stress. In diabetic patients, insufficient induction of Sdf2l1 correlates with progression of insulin resistance and steatohepatitis. Therefore, failure to build an ER stress response in the liver may be a causal factor in obesity-related diabetes and nonalcoholic steatohepatitis, for which Sdf2l1 could serve as a therapeutic target and sensitive biomarker.
Adipocyte differentiation is regulated by various mechanisms, of which mitotic clonal expansion (MCE) is a key step. Although this process is known to be regulated by cell cycle modulators, the ...precise mechanism remains unclear. N
6
-Methyladenosine (m
6
A) posttranscriptional RNA modification, whose methylation and demethylation are performed by respective enzyme molecules, has recently been suggested to be involved in the regulation of adipogenesis. Here, we show that an RNA N
6
-adenosine methyltransferase complex consisting of Wilms' tumor 1-associating protein (WTAP), methyltransferase like 3 (METTL3), and METTL14 positively controls adipogenesis by promoting cell cycle transition in MCE during adipogenesis. WTAP, coupled with METTL3 and METTL14, is increased and distributed in nucleus by the induction of adipogenesis dependently on RNA in vitro. Knockdown of each of these three proteins leads to cell cycle arrest and impaired adipogenesis associated with suppression of cyclin A2 upregulation during MCE, whose knockdown also impairs adipogenesis. Consistent with this, Wtap heterozygous knockout mice are protected from diet-induced obesity with smaller size and number of adipocytes, leading to improved insulin sensitivity. These data provide a mechanism for adipogenesis through the WTAP-METTL3-METTL14 complex and a potential strategy for treatment of obesity and associated disorders.
The STELLA-LONG TERM prospective post-marketing surveillance study assessed ipragliflozin in Japanese patients with type 2 diabetes mellitus (T2DM). This subgroup analysis of patients with liver ...impairment used the final 3-year results. Data on patients, adverse drug reactions (ADRs), and changes in glycemic parameters and liver enzymes (aspartate aminotransferase AST, alanine aminotransferase ALT, gamma-glutamyl transpeptidase γ-GTP and alkaline phosphatase ALP) were collected, and the fatty liver index (FLI) was calculated. In the effectiveness analysis (n = 8,763), baseline liver function was normal in 2,605 patients (ALT <31/<21 U/L men/women) and abnormal in 3,277 (ALT ≥31/≥21 U/L). The abnormal liver function group had higher mean body weight and BMI than the normal liver function group (p < 0.001). In the safety analysis (n = 11,051), urinary tract infections, genital infections and hepatic disorders were more common in the abnormal than normal liver function group (2.25% vs. 1.07%; 1.78% vs. 1.14% and 1.85% vs. 1.01%). In the abnormal liver function group, there were significant (p < 0.001) decreases from baseline at 36 months in AST and ALT (from 38.8 and 53.7 U/L to 29.3 and 37.7 U/L, respectively), γ-GTP (from 75.4 to 51.7 U/L) and ALP (from 254.8 to 234.5 U/L), which were greater than in the normal liver function group. FLI reductions at 36 months were significant (p < 0.001) in subgroups with baseline FLI of ≥30 or ≥60. In conclusion, ipragliflozin improved liver function over 3 years in patients with impaired liver function, although ADRs occurred more frequently than in the normal liver function group.
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