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Brown adipose tissue-enriched lysine methyltransferase EHMT1 is an essential enzyme in the PRDM16–C/EBP-β transcriptional complex that controls brown adipose cell fate and energy metabolism. Control of adipose cell fate Here it is shown that euchromatic histone-lysine N -methyltransferase 1 (EHMT1), an enzyme found at increased levels in brown adipose tissue (BAT), is an essential component of the PRDM16 transcriptional complex that controls brown adipose cell fate. Loss of EHMT1 in brown adipocytes results in loss of brown fat characteristics and induces muscle differentiation in vivo through demethylation of histone 3 Lys 9 in the muscle-selective gene promoters. By contrast, EHMT1 expression switches on the thermogenic gene program in brown adipocytes by stabilizing the PRDM16 protein. Adipose-specific deletion of EHMT1 reduces BAT-mediated adaptive thermogenesis, and causes obesity and insulin resistance. Brown adipose tissue (BAT) dissipates chemical energy in the form of heat as a defence against hypothermia and obesity. Current evidence indicates that brown adipocytes arise from Myf5 + dermotomal precursors through the action of PR domain containing protein 16 (PRDM16) transcriptional complex 1 , 2 . However, the enzymatic component of the molecular switch that determines lineage specification of brown adipocytes remains unknown. Here we show that euchromatic histone-lysine N -methyltransferase 1 (EHMT1) is an essential BAT-enriched lysine methyltransferase in the PRDM16 transcriptional complex and controls brown adipose cell fate. Loss of EHMT1 in brown adipocytes causes a severe loss of brown fat characteristics and induces muscle differentiation in vivo through demethylation of histone 3 lysine 9 (H3K9me2 and 3) of the muscle-selective gene promoters. Conversely, EHMT1 expression positively regulates the BAT-selective thermogenic program by stabilizing the PRDM16 protein. Notably, adipose-specific deletion of EHMT1 leads to a marked reduction of BAT-mediated adaptive thermogenesis, obesity and systemic insulin resistance. These data indicate that EHMT1 is an essential enzymatic switch that controls brown adipose cell fate and energy homeostasis.

Brown adipose tissue (BAT) dissipates chemical energy and generates heat to protect animals from cold and obesity. Rodents possess two types of UCP-1 positive brown adipocytes arising from distinct developmental lineages: \"classical\" brown adipocytes develop during the prenatal stage whereas \"beige\" or \"brite\" cells that reside in white adipose tissue (WAT) develop during the postnatal stage in response to chronic cold or PPARγ agonists. Beige cells' inducible characteristics make them a promising therapeutic target for obesity treatment, however, the relevance of this cell type in humans remains unknown. In the present study, we determined the gene signatures that were unique to classical brown adipocytes and to beige cells induced by a specific PPARγ agonist rosiglitazone in mice. Subsequently we applied the transcriptional data to humans and examined the molecular signatures of human BAT isolated from multiple adipose depots. To our surprise, nearly all the human BAT abundantly expressed beige cell-selective genes, but the expression of classical brown fat-selective genes were nearly undetectable. Interestingly, expression of known brown fat-selective genes such as PRDM16 was strongly correlated with that of the newly identified beige cell-selective genes, but not with that of classical brown fat-selective genes. Furthermore, histological analyses showed that a new beige cell marker, CITED1, was selectively expressed in the UCP1-positive beige cells as well as in human BAT. These data indicate that human BAT may be primary composed of beige/brite cells.

Background The gut environment has been considered to play a role in the development of nonalcoholic steatohepatitis (NASH). α-glucosidase inhibitors (α-GIs) delay carbohydrate absorption and may change the gut environment. We considered that the protective effect of α-GIs against NASH development is related to changes in the gut environment and thus investigated the effects of miglitol, an α-GI, on NASH development and the gut environment. Methods Mice were divided into three groups and fed a normal chow diet (NCD), a high-fat high-sucrose diet (HFHSD), or HFHSD plus 0.04% miglitol (HFHSD plus M) for 12 weeks. Results Insulin resistance developed more in the HFHSD group than in the NCD group, whereas it was suppressed in the HFHSD plus M group. NASH was evaluated histologically, biochemically, and on the basis of messenger RNA expression levels. Miglitol treatment suppressed HFHSD-induced NASH development with the suppression of hepatic Toll-like receptor 4 expression, increased glucagon-like peptide 1 (GLP-1) concentration, and reduced lipopolysaccharide concentration in portal plasma. Regarding the gut environment, the intestinal transit time was shortened and colon inflammation was suppressed in the HFHSD plus M group compared with the HFHSD group. Regarding the gut microbiota, the abundances of Erysipelotrichaceae and Coriobacteriaceae were increased in the HFHSD group compared with the NCD group, whereas the increase was suppressed in the HFHSD plus M group. Conclusions We demonstrated that miglitol has a protective effect against HFHSD-induced NASH development. The increased GLP-1 secretion and the suppression of endotoxemia, associated with the changes in the gut environment, including the gut microbiota, could contribute to the underlying mechanisms.

Brown fat generates heat to protect against cold and obesity. Adrenergic stimulation activates the thermogenic program of brown adipocytes. Although the bioactivity of brown adipose tissue in adult humans had been assumed to very low, several studies using positron emission tomography-computed tomography (PET-CT) have detected bioactive brown adipose tissue in adult humans under cold exposure. In this study, we collected adipose tissues obtained from the perirenal regions of adult patients with pheochromocytoma (PHEO) or non-functioning adrenal tumors (NF). We demonstrated that perirenal brown adipocytes were activated in adult patients with PHEO. These cells had the molecular characteristics of classical brown fat rather than those of beige/brite fat. Expression of brown adipose tissue markers such as uncoupling protein 1 (UCP1) and cell death-inducing DFFA-like effector A (CIDEA) was highly correlated with the amounts of PRD1-BF-1-RIZ1 homologous domain-containing protein-16 (PRDM16) - euchromatic histone-lysine N-methyltransferase 1 (EHMT1) complex, the key transcriptional switch for brown fat development. These results provide novel insights into the reconstruction of human brown adipocytes and their therapeutic application against obesity and its complications such as type 2 diabetes.

The preventive effects of regular exercise on obesity-related health problems are carried over to the non-exercise detraining period, even when physical activity decreases with aging. However, it remains unknown whether regular childhood exercises can be carried over to adulthood. Therefore, this study aimed to investigate the effects of long-term childhood exercise and detraining on lipid accumulation in organs to prevent obesity in adulthood. Four-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were used as obese animals. OLETF rats were allocated into sedentary and exercise groups: exercise from 4- to 12-week-old and detraining from 12- to 20-week-old. At 12-week-old immediately after the exercise period, regular exercise completely inhibited hyperphagia, obesity, enlarged pancreatic islets, lipid accumulation and lobular inflammation in the liver, hypertrophied adipocytes in the white adipose tissue (WAT), and brown adipose tissue (BAT) whitening in OLETF rats. Additionally, exercise attenuated the decrease in the ratio of muscle wet weight to body weight associated with obesity. Decreased food consumption was maintained during the detraining period, which inhibited obesity and diabetes at 20-week-old after the detraining period. Histologically, childhood exercise inhibited the enlargement of pancreatic islets after the detraining period. In addition, inhibition of lipid accumulation was completely maintained in the WAT and BAT after the detraining period. However, the effectiveness was only partially successful in lipid accumulation and inflammation in the liver. The ratio of muscle wet weight to body weight was maintained after detraining. In conclusion, early long-term regular exercise effectively prevents obesity and diabetes in childhood, and its effectiveness can be tracked later in life. The present study suggests the importance of exercise during childhood and adolescence to inhibit hyperphagia-induced lipid accumulation in metabolic-related organs in adulthood despite exercise cessation.

Chewing well is essential for successful diet therapy and control of blood glucose level in patients with diabetes. In addition, long-term hyperglycemia is a risk factor for microvascular complications, which are the main cause of morbidity and mortality in these patients. Hence, it is plausible that masticatory disorder may be relevant to diabetic microvascular complications which is caused by long-term hyperglycemia. The aim of this study was to investigate whether masticatory disorders are relevant to diabetic microvascular complications. This cross-sectional study included 172 patients with type 2 diabetes who underwent educational hospitalization in the Department of Endocrinology and Diabetic Medicine, Hiroshima University Hospital, from April 2016 to March 2020. Masticatory efficiency was determined quantitatively by using the GLUCO SENSOR GS-Ⅱ. Multivariable linear regression models were constructed to examine which factors were related to masticatory efficiency. Statistical significance was defined as a two-sided p value of < 0.05. According to the bivariable analysis, masticatory efficiency was significantly correlated with duration of diabetes (p = 0. 049), number of remaining teeth (p < 0.0001), the number of moving teeth (p = 0.007) and condition of diabetic neuropathy (p < 0.0001). Moreover, the number of remaining teeth (p < 0.0001) and diabetic neuropathy (p = 0.007) remained significantly correlated with masticatory efficiency in the multivariable analysis. For the first time, we demonstrated that patients with type 2 diabetes who developed diabetic neuropathy had significantly reduced masticatory efficiency. Effective mastication is an important factor in successful diet therapy for diabetes. To prevent the progression of diabetic complications, especially in patients with diabetic neuropathy, it may be necessary to combine individualized therapies from dentists and nutritionists with consideration for the level of masticatory dysfunction.

Primary aldosteronism (PA) is the most common form of secondary hypertension, with a prevalence of 5–10% among patients with hypertension. PA is mainly classified into two subtypes: aldosterone-producing adenoma (APA) and bilateral idiopathic hyperaldosteronism. Recent developments in genetic analysis have facilitated the discovery of mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, CLCN2, and CTNNB1 in sporadic or familial forms of PA in the last decade. These findings have greatly advanced our understanding of the mechanism of excess aldosterone synthesis, particularly in APA. Most of the causative genes encode ion channels or pumps, and their mutations lead to depolarization of the cell membrane due to impairment of ion transport. Depolarization activates voltage-gated Ca2+ channels and intracellular calcium signaling and promotes the transcription of aldosterone synthase, resulting in overproduction of aldosterone. In this article, we review recent findings on the genetic and molecular mechanisms of PA.

Aims/Introduction We compared the efficacy and safety of insulin glargine 300 U/mL (Gla300) and insulin degludec U100 (Deg) using a flash glucose monitoring system. Materials and Methods A total of 24 Japanese patients with type 2 diabetes were randomized to receive once‐daily Gla300 (n = 12) or Deg (n = 12) in the morning. The primary end‐points were the mean percentage of time in the target glucose range (70–179 mg/dL) and hypoglycemia (<70 mg/dL), as measured using flash glucose monitoring during the last 7 days of each 14‐day period. Results The percentages of time with glucose levels <70 mg/dL were not significantly different between the two insulin treatments. No significant differences were observed in the percentages of time with glucose levels of 70–179 mg/dL or ≥180 mg/dL. The percentage of time with nocturnal hypoglycemia with Gla300 was significantly lower than that with Deg treatment (P = 0.021). This difference might be attributable to the difference in the duration of action between the two formulations, and the incidence of nocturnal hypoglycemia with Deg treatment was associated with the concomitant use of metformin (P = 0.035). Conclusions The two formulations were comparable in efficacy, whereas the incidence of nocturnal hypoglycemia was significantly lower with Gla300. Thus, the present study suggests that, although Gla300 and Deg are comparable long‐acting insulin analogs, Gla300 is safer with respect to the incidence of hypoglycemia. We carried out an open‐label, parallel‐group, two‐period crossover study of 24 Japanese patients with type 2 diabetes to compare their efficacy and safety. We found that Gla300 and Deg are comparable in maintaining blood glucose levels within the normal range using flash glucose monitoring.

Aims/Introduction High 1‐h plasma glucose levels have an increased risk of type 2 diabetes. To determine the pathophysiological features in participants with normal glucose tolerance (NGT) with 1‐h hyperglycemia (HG), we investigated the variability in the glucagon and insulin secretions after oral glucose loading and nutrient survey. Materials and Methods A 75‐g oral glucose tolerance test (OGTT) was performed in Japanese Americans (aged 40–75 years), enrolled in medical surveys conducted in 2015. We recruited only participants with NGT defined as fasting glucose values <110 mg/dL and 2‐h glucose levels <140 mg/dL. We evaluated homeostatic model assessment for insulin resistance (HOMA‐IR), insulin sensitivity index (MATSUDA‐Index), insulin, and glucagon (GCG) secretions during the 75‐g OGTT and compared them between 1‐h serum glucose values: <155 mg/dL (1‐h non‐hyperglycemia: NHG, n = 76) and 1‐h serum glucose values: ≥155 mg/dL (HG, n = 41). We also conducted a dietary intake survey to determine the association between 1‐h serum glucose and nutritional intake in the usual diet. Results The HG group demonstrated significant insulin resistance compared to the NHG group. Two‐h GCG levels were significantly lower in the HG group. Additionally, low vegetable fat intake was significantly associated with 1‐h HG after adjusting for sex, age, and body mass index. Conclusions Insulin resistance is already present in the HG group. Vegetable fat intake may be associated with glucose metabolism regardless of clinical background. High 1‐h plasma glucose levels have an increased risk of type 2 diabetes. We recruited only participants with NGT defined as fasting glucose values <110 mg/dL and 2‐h glucose levels <140 mg/dL after 75‐g oral glucose loading. We evaluated insulin resistance, insulin, and glucagon secretions during the 75‐g oral glucose tolerance test (OGTT) and compared them between 1‐h serum glucose values: <155 mg/dL (1‐h non‐hyperglycemia: NHG) and 1‐h serum glucose values: ≥155 mg/dL (HG). We also conducted a dietary intake survey. The HG group demonstrated significant insulin resistance, lower 2‐h glucagon levels, and lower vegetable fat intakes. These findings contribute to our understanding of the pathophysiological features of individuals with NGT with HG, who are at high risk of developing diabetes.

Aims/Introduction Our previous survey of two Japanese populations, with different lifestyles but identical genetic dispositions, showed that Japanese Americans had different dietary intakes and higher prevalences of obesity and diabetes mellitus, compared with the native Japanese population. The present study examined whether Westernized dietary habits could affect the development of obesity or diabetes. Materials and methods This study included 765 individuals with normal glucose tolerance at baseline medical examinations (1986 or 1989 in Los Angeles and in 1988 or 1992 in Hawaii) who subsequently completed follow‐up medical examinations several years later. The participants were categorized at baseline as “lean” (576 individuals, body mass index of <25 kg/m2) or “obese” (189 individuals, body mass index of ≥25 kg/m2). Nutrient intakes were analyzed for associations with the development of obesity or diabetes using Cox's proportional hazard model. Results A total of 41 lean participants developed diabetes, which was not associated with any nutrient intakes (mean follow up 10.8 ± 6.6 years). A total of 36 obese participants developed diabetes, which was positively associated with intakes of animal protein, animal fat and saturated fatty acid (mean follow up 10.7 ± 6.3 years). A total of 85 lean participants became obese, which was positively associated with intakes of simple carbohydrates, sugar and fructose, as well as inversely associated with intakes of vegetable protein and complex carbohydrates (mean follow up 10.4 ± 6.5 years). Conclusions In the Japanese Americans, different nutrient intakes affected the development of obesity and diabetes. Furthermore, the associations of nutrient intakes with diabetes development varied according to the presence or absence of obesity. Among ‘lean’ subjects (BMI of <25 kg/m2), nutrient intakes were not associated with the development of diabetes, although the development of obesity was positively associated with intakes of simple carbohydrates and negatively associated with low intakes of complex carbohydrates and vegetable protein. Among ‘obese’ subjects (BMI of ≥25 kg/m2), the development of diabetes was associated positively with high intakes of animal protein, animal fat, and saturated fatty acids.