Impaired hepatic glucose uptake (HGU) causes postprandial hyperglycemia in type 2 diabetes. Here, we show that diminished hepatic Sirt2 activity impairs HGU in obese diabetic mice. Hepatic Sirt2 ...overexpression increases HGU in high-fat diet (HFD)-fed obese diabetic mice and mitigates their impaired glucose tolerance. Hepatic Sirt2 knockdown in non-diabetic mice reduces HGU and causes impaired glucose tolerance. Sirt2 promotes glucose-dependent HGU by deacetylating K126 of glucokinase regulatory protein (GKRP). Glucokinase and GKRP glucose-dependent dissociation is necessary for HGU but is inhibited in hepatocytes derived from obese diabetic mice, depleted of Sirt2 or transfected with GKRP acetylation-mimicking mutants. GKRP deacetylation-mimicking mutants dissociate from glucokinase in a glucose concentration-dependent manner in obese diabetic mouse-derived hepatocytes and increase HGU and glucose tolerance in HFD-induced or db/db obese diabetic mice. We demonstrate that Sirt2-dependent GKRP deacetylation improves impaired HGU and suggest that it may be a therapeutic target for type 2 diabetes.
The hallmark of type 2 diabetes is excessive hepatic glucose production. Several transcription factors and coactivators regulate this process in cultured cells. But gene ablation experiments have ...yielded few clues as to the physiologic mediators of this process in vivo. We show that inactivation of the gene encoding forkhead protein Foxo1 in mouse liver results in 40% reduction of glucose levels at birth and 30% reduction in adult mice after a 48 hr fast. Gene expression and glucose clamp studies demonstrate that Foxo1 ablation impairs fasting- and cAMP-induced glycogenolysis and gluconeogenesis. Pgc1α is unable to induce gluconeogenesis in Foxo1-deficient hepatocytes, while the cAMP response is significantly blunted. Conversely, Foxo1 deletion in liver curtails excessive glucose production caused by generalized ablation of insulin receptors and prevents neonatal diabetes and hepatosteatosis in insulin receptor knockout mice. The data provide a unifying mechanism for regulation of hepatic glucose production by cAMP and insulin.
During fasting, dephosphory- lation-dependent activation of the CREB coactivator CRTC2 by glu- cagon is crucial for activation of the hepatic gluconeogenic program, but the molecular mechanism by ...which hormones regulate CRTC2 activation remains unclear. A recent report in Nature showed that PKA- dependent phosphorylation of the inositol-1,4,5-trisphosphate receptor （InsP3R） induces Ca2＋ mobilization, leading to increase in the phosphatase activity of calcineurin and the subse- quent dephosphorylation of CRTC2, thereby resulting in the induction of gluconeogenic gene expression. It also showed that insulin-dependent phosphorylation of InsP3R by Akt in- hibits Ca2＋ mobilization and CRTC2 dephosphorylation, resulting in the suppression of gluconeogenesis.
Adipose tissue resident macrophages have important roles in the maintenance of tissue homeostasis and regulate insulin sensitivity for example by secreting pro-inflammatory or anti-inflammatory ...cytokines. Here, we show that M2-like macrophages in adipose tissue regulate systemic glucose homeostasis by inhibiting adipocyte progenitor proliferation via the CD206/TGFβ signaling pathway. We show that adipose tissue CD206
cells are primarily M2-like macrophages, and ablation of CD206
M2-like macrophages improves systemic insulin sensitivity, which was associated with an increased number of smaller adipocytes. Mice genetically engineered to have reduced numbers of CD206
M2-like macrophages show a down-regulation of TGFβ signaling in adipose tissue, together with up-regulated proliferation and differentiation of adipocyte progenitors. Our findings indicate that CD206
M2-like macrophages in adipose tissues create a microenvironment that inhibits growth and differentiation of adipocyte progenitors and, thereby, control adiposity and systemic insulin sensitivity.Adipose tissue contains macrophages that can influence both local and systemic metabolism via the secretion of cytokines. Here, Nawaz et al. report that M2-like macrophages, present in adipose tissue, create a microenvironment that inhibits proliferation of adipocyte progenitors due to the secretion of TGF-β1.
In yeast, worms, and flies, an extra copy of the gene encoding the Sirtuin
Sir2 increases metabolic efficiency, as does administration of polyphenols like resveratrol, thought to act through ...Sirtuins. But evidence that Sirtuin gain of function results in increased metabolic efficiency in mammals is limited. We generated transgenic mice with moderate overexpression of SirT1, designed to mimic the Sirtuin gain of function that improves metabolism in
C. elegans. These mice exhibit normal insulin sensitivity but decreased food intake and locomotor activity, resulting in decreased energy expenditure. However, in various models of insulin resistance and diabetes, SirT1 transgenics display improved glucose tolerance due to decreased hepatic glucose production and increased adiponectin levels, without changes in body weight or composition. We conclude that SirT1 gain of function primes the organism for metabolic adaptation to insulin resistance, increasing hepatic insulin sensitivity and decreasing whole-body energy requirements. These findings have important implications for Sirtuin-based therapies in humans.
Hepatocellular death increases with hepatic steatosis aggravation, although its regulation remains unclear. Here we show that hepatic steatosis aggravation shifts the hepatocellular death mode from ...apoptosis to necroptosis, causing increased hepatocellular death. Our results reveal that the transcription factor ATF3 acts as a master regulator in this shift by inducing expression of RIPK3, a regulator of necroptosis. In severe hepatic steatosis, after partial hepatectomy, hepatic ATF3-deficient or -overexpressing mice display decreased or increased RIPK3 expression and necroptosis, respectively. In cultured hepatocytes, ATF3 changes TNFα-dependent cell death mode from apoptosis to necroptosis, as revealed by live-cell imaging. In non-alcoholic steatohepatitis (NASH) mice, hepatic ATF3 deficiency suppresses RIPK3 expression and hepatocellular death. In human NASH, hepatocellular damage is correlated with the frequency of hepatocytes expressing ATF3 or RIPK3, which overlap frequently. ATF3-dependent RIPK3 induction, causing a modal shift of hepatocellular death, can be a therapeutic target for steatosis-induced liver damage, including NASH.
Aims/Introduction
Non‐alcoholic steatohepatitis (NASH), which occurs in association with insulin resistance and hepatic fat accumulation, is characterized by chronic liver injury and fibrosis. NASH ...onset and progression is closely related to hepatic inflammation, which is partly regulated by the vagus nerve through the α7 nicotinic acetylcholine receptor (α7nAchR). Hepatic α7nAchR action is impeded in obesity and insulin resistance. In the present study, using α7nAchR knockout (α7KO) mice, we elucidated the effect of α7nAchR deficiency on NASH‐related inflammation and fibrosis.
Materials and Methods
α7KO mice were fed an atherogenic high‐fat diet (AD) for 32 weeks or methionine/choline‐deficient diet (MCD) for 6 weeks, both of which induce NASH. Mice were then examined for the degree of NASH‐related inflammation and fibrosis by hepatic gene expression analysis and Sirius red histological staining.
Results
Hepatic triglyceride accumulation and elevated plasma transaminase levels were observed in both AD and MCD mice, but the plasma transaminase level increase was higher in α7KO mice than in control mice. α7KO mice fed an AD showed significant upregulation of the Col1a1 gene encoding alpha‐1 type I collagen, which is involved in liver fibrosis, and the Ccl2 gene encoding C‐C motif chemokine ligand 2, a pro‐inflammatory chemokine; α7KO mice fed an MCD had significant upregulation of the Col1a1 gene and the Tnf gene, an inflammatory cytokine. Histological analysis showed that AD and MCD exacerbated liver fibrosis in α7KO mice.
Conclusions
The results of this study suggest that α7nAchR deficiency exacerbates hepatic inflammation and fibrosis in a diet‐induced mouse model of NASH.
The vagus nerve suppresses hepatic inflammation through α7nAchR. α7nAchR deficiency exacerbates hepatic inflammation and fibrosis in a diet‐induced mouse model of NASH, suggesting that α7nAchR action plays an important role in NASH onset and progression.
General control nonderepressible 5 (GCN5, also known as Kat2a) and p300/CBP-associated factor (PCAF, also known as Kat2b) are two homologous acetyltransferases. Both proteins share similar domain ...architecture consisting of a PCAF N-terminal (PCAF_N) domain, acetyltransferase domain, and a bromodomain. PCAF also acts as a ubiquitin E3 ligase whose activity is attributable to the PCAF_N domain, but its structural aspects are largely unknown. Here, we demonstrated that GCN5 exhibited ubiquitination activity in a similar manner to PCAF and its activity was supported by the ubiquitin-conjugating enzyme UbcH5. Moreover, we determined the crystal structure of the PCAF_N domain at 1.8 Å resolution and found that PCAF_N domain folds into a helical structure with a characteristic binuclear zinc region, which was not predicted from sequence analyses. The zinc region is distinct from known E3 ligase structures, suggesting this region may form a new class of E3 ligase. Our biochemical and structural study provides new insight into not only the functional significance of GCN5 but also into ubiquitin biology.
Aim
To investigate (1) the association of lifestyle changes and living and working conditions with glycemic control and (2) whether treatment was intensified appropriately in patients with diabetes ...under the first COVID‐19 state of emergency in Japan.
Materials and Methods
A total of 321 participants were included. Participants completed a questionnaire regarding lifestyle changes, including diet, physical activity, and living and working conditions during the COVID‐19 pandemic. The change in hemoglobin A1c (HbA1c) levels was estimated before (June 1, 2019 to August 31, 2019) and during (June 1, 2020 to August 31, 2020) the pandemic. Factors associated with changes in HbA1c levels were examined by multiple linear regression analysis. The proportion of patients who received treatment intensification for diabetes was compared between before and during the pandemic.
Results
There was no significant change in HbA1c levels before the pandemic and during the pandemic (7.13 ± 0.98% vs 7.18 ± 1.01%, P = 0.186). Teleworking (estimate 0.206, P = 0.004) and living with a dog (estimate −0.149, P = 0.038) were significantly associated with changes in HbA1c levels after adjusting for covariates. There was no significant difference in the proportion of patients who received treatment intensification for diabetes during the pandemic and before the pandemic in either the elderly or non‐elderly patients.
Conclusions
Overall glycemic control did not worsen during the pandemic. Nonetheless, environmental factors, including telework, were found to influence glycemic control in patients with diabetes. Further studies are needed to clarify whether the COVID‐19 pandemic could affect treatment intensification for diabetes.
The study investigated (1) the association of lifestyle changes and living and working conditions with glycemic control and (2) whether treatment was intensified appropriately in diabetes patients under the first COVID‐19 state of emergency in Japan. Teleworking and living with a dog were positively and negatively associated with changes in HbA1c levels, respectively. The proportion of patients who received treatment intensification for diabetes during the pandemic was slightly lower than that before the pandemic, but the difference did not reach statistical significance.
Sodium-glucose cotransporter 2 inhibitor (SGLT2i) consistently reduces blood glucose levels in type 2 diabetes mellitus but increases hepatic gluconeogenic gene expression and glucose production, ...offsetting its glucose-lowering effect. This study aimed to elucidate the effect of SGLT2i on hepatic gluconeogenic response and its mechanism in both insulin-sensitive and insulin-resistant states. A hepatic mouse model was generated to show liver-specific expression of Gaussia luciferase (GLuc) driven by the gluconeogenic enzyme gene G6pc promoter. Hepatic gluconeogenic response was evaluated by measuring plasma GLuc activity. SGLT2i was given to lean and obese mice in single gavage administration or 4-week dietary administration with controlled feeding every 3 hours. In lean mice, single-dose SGLT2i increased plasma GLuc activity from 2 hours after administration, decreasing blood glucose and plasma insulin from 1 to 2 hours after administration. In obese mice, which had higher plasma GLuc activity than lean ones, SGLT2i did not further increase GLuc activity despite decreased blood glucose and plasma insulin. Hepatic Akt and GSK3β phosphorylation was attenuated by single-dose SGLT2i in lean mice in accordance with the plasma insulin decrease, but not in obese mice. Long-term SGLT2i administration, which increased plasma GLuc activity in lean mice, decreased it in obese mice from 3 weeks after initiation, with increased hepatic Akt and GSK3β phosphorylation. In conclusion, single SGLT2i administration increases hepatic gluconeogenic response in lean insulin-sensitive mice, but not in obese insulin-resistant mice. Long-term SGLT2i administration relieves obesity-induced upregulation of the hepatic gluconeogenic response by restoring impeded hepatic insulin signaling in obese insulin-resistant mice.
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