A gut–brain neural circuit controlled by intestinal gluconeogenesis is crucial in metabolic health

Soty, Maud; Penhoat, Armelle; Amigó-Correig, Marta; Vinera, Jennifer; Sardella, Anne; Vullin-Bouilloux, Fanny; Zitoun, Carine; Houberdon, I.; Mithieux, Gilles

doi:10.1016/j.molmet.2014.12.009

Cited by 54 publications

(57 citation statements)

References 41 publications

(66 reference statements)

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“…Type 2 diabetes (T2D) is a growing global health problem, affecting over 336 million people worldwide [ 1 – 3 ]. T2D is a metabolic disorder characterized by chronic hyperglycemia resulting from insulin resistance and impaired insulin secretion [ 4 , 5 ]. Recent epidemiological and experimental studies have also revealed that T2D is closely associated with long-term damage, dysfunction, and failure of various organs [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…T2D is a metabolic disorder characterized by chronic hyperglycemia resulting from insulin resistance and impaired insulin secretion [ 4 , 5 ]. Recent epidemiological and experimental studies have also revealed that T2D is closely associated with long-term damage, dysfunction, and failure of various organs [ 5 , 6 ]. Among them, chronic liver disease is a major complication of T2D since liver is the main target organ for insulin in regulating myriad metabolic processes such as glycogen storage and gluconeogenesis.…”

Section: Introductionmentioning

confidence: 99%

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Adipose tissue-derived stem cells ameliorate hyperglycemia, insulin resistance and liver fibrosis in the type 2 diabetic rats

et al. 2017

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BackgroundType 2 diabetes (T2D) is closely associated with liver fibrosis, but no effective treatments are currently available. This study was designed to investigate the therapeutic effects of ADSCs on insulin resistance, hyperglycemia, and liver fibrosis on T2D rats.MethodsWe first established a T2D rat model with liver fibrosis by using the combination of a high-fat diet (HFD), low-dose streptozotocin (STZ), and carbon tetrachloride (CCl4). Subsequently, the model rats were administrated by tail vein injection of PBS or ADSCs, respectively. Thereafter, insulin resistance and liver function were assessed by biochemical analysis, ELISA, histopathological examination, and q-PCR assay, respectively. Moreover, the molecular mechanisms of ADSCs on the effect of the TGF-β1/SMAD3 signaling pathway were further analyzed.ResultsOur data showed that ADSC transplantation significantly alleviated insulin resistance and hyperglycemia in the liver-injured T2D rats. We also found that ADSC transplantation could attenuate liver injury by improving liver function and inhibiting pathological changes of liver fibrosis, as well as through downregulation of TGF-β1 and phosphorylated SMAD3 both in vitro and in vivo.ConclusionsThese findings suggested that ADSC transplantation can ameliorate insulin resistance, hyperglycemia, and liver fibrosis via suppressing TGF-β1/SMAD3 signaling, which may provide a potential treatment strategy for liver fibrosis of T2D.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0743-7) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adipose tissue-derived stem cells ameliorate hyperglycemia, insulin resistance and liver fibrosis in the type 2 diabetic rats

et al. 2017

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“…What's more, in the rat lacking the key enzyme of intestinal gluconeogenesis, Phosphorylation of STAT3 decrease, which is a key intermediate in the hypothalamic leptin signal cascade. This change is restored after intestinal infusion of glucose [48]. This also indicates that intestinal gluconeogenesis also improves the sensitivity of the hypothalamic leptin signaling pathway, and the hypothalamic leptin action plays a very important role in the regulation of the body's glucose homeostasis.…”

Section: Intestinal Gluconeogenesis and Hypothalamic Regulationmentioning

confidence: 76%

Gastric Bypass Surgery Regulates Glucose Homeostasis Through the Hypothalamus

Quan¹

2019

CMR

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To explore the role of blood glucose regulation in gastric bypass surgery is a hot point in the treatment of diabetes in recent years. Current evidence is very clear that the gastric bypass surgery is one of the most promising therapy to cure type 2 diabetes. However, the mechanisms are not yet understood. Studying the mechanism of surgical treatment can not only understand the pathogenesis of diabetes, but also have important scientific and practical significance for clinically and safely carrying out this therapy. As is known to all, the body's energy metabolism and glucose homeostasis are regulated by the hypothalamus. Thus, we summarize the process mechanism of central regulation of glucose homeostasis in post-surgery and find that the hypothalamus after gastric bypass surgery showed enhanced expression of peripheral signal receptors, enhancement of leptin signal and insulin signal, and expression changes of certain related genes, then issued neuroendocrine signals to control peripheral insulin sensitivity and glucose metabolism. Then, we prove that the improvement of peripheral metabolic status is caused by the decisive role of central regulation in post-surgery. These funding provide scientific basis to improve the understanding of the neuroendocrine mechanism of diabetes and the development of clinical implication of gastric bypass surgery.

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“…Indeed, we found decreased Gck mRNA expression and no difference in GK activity in KI-G6pc -/- mice compared to WT mice during fasting. We previously reported the decrease in hepatic insulin sensitivity of EGP in intestine-specific G6pc knockout mice [28] . These findings firmly indicated that upregulation of intestinal gluconeogenesis is required to enhance GK activity during fasting.…”

Section: Discussionmentioning

confidence: 95%

“…We recently showed that deficit in intestinal gluconeogenesis was involved in the attenuation of hepatic insulin signaling via a modulation of sympathetic tone [28] . Moreover, fiber-enriched diets were shown to up-regulate intestinal gluconeogenesis, resulting in enhancement of hepatic insulin signaling [10] .…”

Section: Resultsmentioning

confidence: 99%

The role of kidney in the inter-organ coordination of endogenous glucose production during fasting

Kaneko

Soty

Zitoun

et al. 2018

Molecular Metabolism

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ObjectiveThe respective contributions to endogenous glucose production (EGP) of the liver, kidney and intestine vary during fasting. We previously reported that the deficiency in either hepatic or intestinal gluconeogenesis modulates the repartition of EGP via glucagon secretion (humoral factor) and gut–brain–liver axis (neural factor), respectively. Considering renal gluconeogenesis reportedly accounted for approximately 50% of EGP during fasting, we examined whether a reduction in renal gluconeogenesis could promote alterations in the repartition of EGP in this situation.MethodsWe studied mice whose glucose-6-phosphatase (G6Pase) catalytic subunit (G6PC) is specifically knocked down in the kidneys (K-G6pc-/- mice) during fasting. We also examined the additional effects of intestinal G6pc deletion, renal denervation and vitamin D administration on the altered glucose metabolism in K-G6pc-/- mice.ResultsCompared with WT mice, K-G6pc-/- mice exhibited (1) lower glycemia, (2) enhanced intestinal but not hepatic G6Pase activity, (3) enhanced hepatic glucokinase (GK encoded by Gck) activity, (4) increased hepatic glucose-6-phosphate and (5) hepatic glycogen spared from exhaustion during fasting. Increased hepatic Gck expression in the post-absorptive state could be dependent on the enhancement of insulin signal (AKT phosphorylation) in K-G6pc-/- mice. In contrast, the increase in hepatic GK activity was not observed in mice with both kidney- and intestine-knockout (KI-G6pc-/- mice). Hepatic Gck gene expression and hepatic AKT phosphorylation were reduced in KI-G6pc-/- mice. Renal denervation by capsaicin did not induce any effect on glucose metabolism in K-G6pc-/- mice. Plasma level of 1,25 (OH)2 D3, an active form of vitamin D, was decreased in K-G6pc-/- mice. Interestingly, the administration of 1,25 (OH)2 D3 prevented the enhancement of intestinal gluconeogenesis and hepatic GK activity and blocked the accumulation of hepatic glycogen otherwise observed in K-G6pc-/- mice during fasting.ConclusionsA diminution in renal gluconeogenesis that is accompanied by a decrease in blood vitamin D promotes a novel repartition of EGP among glucose producing organs during fasting, featured by increased intestinal gluconeogenesis that leads to sparing glycogen stores in the liver. Our data suggest a possible involvement of a crosstalk between the kidneys and intestine (via the vitamin D system) and the intestine and liver (via a neural gut-brain axis), which might take place in the situations of deficient renal glucose production, such as chronic kidney disease.

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A gut–brain neural circuit controlled by intestinal gluconeogenesis is crucial in metabolic health

Cited by 54 publications

References 41 publications

Adipose tissue-derived stem cells ameliorate hyperglycemia, insulin resistance and liver fibrosis in the type 2 diabetic rats

Adipose tissue-derived stem cells ameliorate hyperglycemia, insulin resistance and liver fibrosis in the type 2 diabetic rats

Gastric Bypass Surgery Regulates Glucose Homeostasis Through the Hypothalamus

The role of kidney in the inter-organ coordination of endogenous glucose production during fasting

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