Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPARγ (peroxisome proliferator-activated receptor γ) at ...serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues. Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPARγ, such as the thiazolidinediones and PPARγ partial agonists or non-agonists. For a better understanding of the importance of this obesity-linked PPARγ phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPARγ phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPARγ in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK markedly improves insulin resistance in both obese wild-type and ob/ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPARγ function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Obesity is associated with a chronic state of low-grade inflammation and progressive tissue infiltration by immune cells and increased expression of inflammatory cytokines. It is established that ...interleukin 6 (IL6) regulates multiple aspects of metabolism, including glucose disposal, lipolysis, oxidative metabolism, and energy expenditure. IL6 is secreted by many tissues, but the role of individual cell types is unclear. We tested the role of specific cells using a mouse model with conditional expression of the Il6 gene. We found that IL6 derived from adipocytes increased, while IL6 derived from myeloid cells and muscle suppressed, macrophage infiltration of adipose tissue. These opposite actions were associated with a switch of IL6 signaling from a canonical mode (myeloid cells) to a noncanonical trans-signaling mode (adipocytes and muscle) with increased expression of the ADAM10/17 metalloprotease that promotes transsignaling by the soluble IL6 receptor α. Collectively, these data demonstrate that the source of IL6 production plays a major role in the physiological regulation of metabolism.
ABSTRACT
Lipodystrophy is a rare disorder characterized by complete or partial loss of adipose tissue. Patients with lipodystrophy exhibit hypertriglyceridemia, severe insulin resistance, type 2 ...diabetes, and nonalcoholic steatohepatitis (NASH). Efforts to ameliorate NASH in lipodystrophies with pharmacologic agents have met with limited success. We examined whether a controlled‐release mitochondrial protonophore (CRMP) that produces mild liver‐targeted mitochondrial uncoupling could decrease hypertriglyceridemia and reverse NASH and diabetes in a mouse model (fatless AZIP/F‐1 mice) of severe lipodystrophy and diabetes. After 4 wk of oral CRMP (2 mg/kg body weight per day) or vehicle treatment, mice underwent hyperinsulinemic‐euglycemic clamps combined with radiolabeled glucose to assess liver and muscle insulin responsiveness and tissue lipid measurements. CRMP treatment reversed hypertriglyceridemia and insulin resistance in liver and skeletal muscle. Reversal of insulin resistance could be attributed to reductions in diacylglycerol content and reduced PKC‐ε and PKC‐θ activity in liver and muscle respectively. CRMP treatment also reversed NASH as reflected by reductions in plasma aspartate aminotransferase and alanine aminotransferase concentrations; hepatic steatosis; and hepatic expression of IL‐1α, ‐β, ‐2, ‐4, ‐6, ‐10, ‐12, CD69, and caspase 3 and attenuated activation of the IRE‐1α branch of the unfolded protein response. Taken together, these results provide proof of concept for the development of liver‐targeted mitochondrial uncoupling agents as a potential novel therapy for lipodystrophy‐associated hypertriglyceridemia, NASH and diabetes.—Abulizi, A., Perry, R. J., Camporez, J. P. G., Jurczak, M. J., Petersen, K. F., Aspichueta, P., Shulman, G. I. A controlled‐release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice. FASEB J. 31, 2916–2924 (2017). www.fasebj.org
Impaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains ...unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase. Insulin’s ability to suppress hepatic acetyl CoA, PC activity, and lipolysis was lost in high-fat-fed rats, a phenomenon reversible by IL-6 neutralization and inducible by IL-6 infusion. Taken together, these data identify WAT-derived hepatic acetyl CoA as the main regulator of HGP by insulin and link it to inflammation-induced hepatic insulin resistance associated with obesity and T2D.
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•Insulin inhibits gluconeogenesis by suppressing lipolysis and hepatic acetyl CoA•Hyperglycemia associated with HFD is due to increased WAT-derived hepatic acetyl CoA•ATGL KOs are protected from HFD-induced insulin resistance due to decreased lipolysis•mφJNK KOs are protected from HFD-induced insulin resistance due to decreased lipolysis
Metabolic abnormalities associated with a high-fat diet are found to be driven by increased hepatic acetyl CoA levels, which are shown to be a consequence of white adipose tissue inflammation and inappropriately increased lipolysis.
Leptin treatment reverses hyperglycemia in animal models of poorly controlled type 1 diabetes (T1D), spurring great interest in the possibility of treating patients with this hormone. The ...antidiabetic effect of leptin has been postulated to occur through suppression of glucagon production, suppression of glucagon responsiveness or both; however, there does not appear to be a direct effect of leptin on the pancreatic alpha cell. Thus, the mechanisms responsible for the antidiabetic effect of leptin remain poorly understood. We quantified liver-specific rates of hepatic gluconeogenesis and substrate oxidation in conjunction with rates of whole-body acetate, glycerol and fatty acid turnover in three rat models of poorly controlled diabetes, including a model of diabetic ketoacidosis. We show that the higher rates of hepatic gluconeogenesis in all these models could be attributed to hypoleptinemia-induced activity of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in higher rates of adipocyte lipolysis, hepatic conversion of glycerol to glucose through a substrate push mechanism and conversion of pyruvate to glucose through greater hepatic acetyl-CoA allosteric activation of pyruvate carboxylase flux. Notably, these effects could be dissociated from changes in plasma insulin and glucagon concentrations and hepatic gluconeogenic protein expression. All the altered systemic and hepatic metabolic fluxes could be mimicked by infusing rats with Intralipid or corticosterone and were corrected by leptin replacement. These data demonstrate a critical role for lipolysis and substrate delivery to the liver, secondary to hypoleptinemia and HPA axis activity, in promoting higher hepatic gluconeogenesis and hyperglycemia in poorly controlled diabetes.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Mononuclear phagocytes (MNPs) are a highly heterogeneous group of cells that play important roles in maintaining the body’s homeostasis. Here, we found CD301b (also known as MGL2), a lectin commonly ...used as a marker for alternatively activated macrophages, was selectively expressed by a subset of CD11b+CD11c+MHCII+ MNPs in multiple organs including adipose tissues. Depleting CD301b+ MNPs in vivo led to a significant weight loss with increased insulin sensitivity and a marked reduction in serum Resistin-like molecule (RELM) α, a multifunctional cytokine produced by MNPs. Reconstituting RELMα in CD301b+ MNP-depleted animals restored body weight and normoglycemia. Thus, CD301b+ MNPs play crucial roles in maintaining glucose metabolism and net energy balance.
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•In vivo depletion of CD301b+ MNPs results in reduced food intake and weight loss•Depletion of CD301b+ MNPs reduces blood glucose and increases insulin sensitivity•CD301b+ MNP-depleted mice have decreased serum RELMα concentration•Reconstitution of RELMα restores body weight and normoglycemia
Mononuclear phagocytes play an integral role in the regulation of whole-body metabolism. Kumamoto et al. demonstrated that CD301b+ mononuclear phagocytes in adipose tissues secrete resistin-like molecule alpha (RELM-α) to maintain positive energy balance.
One of the consequences of sedentary lifestyle and consumption of a high-fat diet is Nonalcoholic Fatty Liver Disease (NAFLD), which affects approximately 30% of adults and up to 10% of children in ...developed countries. Interestingly, metabolic complications, such as insulin resistance and obesity, are less frequent in young women than in men of the same age or in postmenopausal women. In fact, reduced estrogen concentration during menopause is associated with increased visceral fat, metabolic diseases, insulin resistance, and T2DM. However, how estradiol is related to the development and progression of NAFLD remains unknown. Therefore, the general objective of this project was to study (in vivo) the effects of estrogen receptor alpha (ERα) ablation on hepatic energy metabolism. To this end, C57BL6 mice with ERα deletion specifically in the liver were generated using the Cre-Lox system (LERaKO). Sixth-week-old mice (Control and LERaKO mice) were fed a high-fat diet (HFD) with 45% fat. LERaKO mice displayed no difference in final body weight compared with control mice after four weeks of HFD feeding. A glucose tolerance test (GTT) was also performed after four weeks of HFD feeding. LERaKO mice displayed an increase in glucose intolerance by ~21% (P<0.05) compared with control mice, despite showing no difference in insulin secretion over the course of the GTT. Interestingly, we observed an increase in hepatic triglyceride (TAG) content by ~157% (P<0.05) in LERaKO mice compared with control mice and a decrease in plasma triglyceride concentration. We did not observe a significant difference in the expression of pro- and anti-inflammatory genes, but observed a significant increase in the expression of genes related to lipid synthesis and gluconeogenesis (P<0.05). Taken together, these data confirm the hypothesis that ERα plays a pivotal role in hepatic metabolism in mice, as liver-specific ERα ablation leads to glucose intolerance and hepatic steatosis.
Disclosure
F. Sucupira: None. L. Araujo: None. J. Camporez: None.
Funding
FAPESP (2021/02638-9)
The cJun NH
-terminal kinase (JNK) signaling pathway is activated by metabolic stress and promotes the development of metabolic syndrome, including hyperglycemia, hyperlipidemia, and insulin ...resistance. This integrated physiological response involves cross-talk between different organs. Here we demonstrate that JNK signaling in adipocytes causes an increased circulating concentration of the hepatokine fibroblast growth factor 21 (FGF21) that regulates systemic metabolism. The mechanism of organ crosstalk is mediated by a feed-forward regulatory loop caused by JNK-regulated FGF21 autocrine signaling in adipocytes that promotes increased expression of the adipokine adiponectin and subsequent hepatic expression of the hormone FGF21. The mechanism of organ cross-talk places circulating adiponectin downstream of autocrine FGF21 expressed by adipocytes and upstream of endocrine FGF21 expressed by hepatocytes. This regulatory loop represents a novel signaling paradigm that connects autocrine and endocrine signaling modes of the same hormone in different tissues.
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