Effects of hepatic glycogen on food intake and glucose homeostasis are mediated by the vagus nerve in mice

López-Soldado, Iliana; Fuentes-Romero, Rebeca; Durán, Jordi; Guinovart, Joan J.

doi:10.1007/s00125-017-4240-4

Cited by 35 publications

(30 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Adenine nucleotide concentrations in the mouse liver are highly sensitive to acute physiological stressors, as well as to metabolic disease, and the hepatic energy state is substantially reduced following fasting [5]. Previous studies from our laboratory have demonstrated that liver glycogen levels regulate hepatic ATP content in mice fed a high‐fat diet (HFD) [8,11]. In the present study, we show that liver glycogen contributes to maintaining the hepatic energy charge after long‐term fasting (36 h).…”

Section: Discussionsupporting

confidence: 58%

“…The dried papers were incubated with amyloglucosidase (25 U·L −1 Sigma) in 100 m m sodium acetate buffer at pH 4.8 to digest glycogen, and glucose release was determined by the reaction with hexokinase and glucose 6‐phosphate dehydrogenase, following the original method described by Chan [10]. The intracellular concentration of ATP and AMP was measured in perchloric acid extracts by HPLC, as previously described [11]. Lactate was measured in perchloric acid extracts using a commercial spectrophotometric kit (Horiba, ABX, Montpellier, France).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Maintenance of liver glycogen during long‐term fasting preserves energy state in mice

et al. 2020

Self Cite

View full text Add to dashboard Cite

Glycogen shortage during fasting coincides with dramatic changes in hepatic adenine nucleotide levels. The aim of this work was to study the relevance of liver glycogen in the regulation of the hepatic energy state during food deprivation. To this end, we examined the response of mice with sustained increased liver glycogen content to prolonged fasting. In order to increase hepatic glycogen content, we generated mice that overexpress protein targeting to glycogen (PTG) in the liver (PTG OE mice). Control and PTG OE mice were fed ad libitum or fasted for 36 h. Upon fasting, PTG OE mice retained significant hepatic glycogen stores and maintained hepatic energy status. Furthermore, we show that liver glycogen controls insulin sensitivity, gluconeogenesis, lipid metabolism, and ketogenesis upon nutrient deprivation.

show abstract

Section: Discussionsupporting

confidence: 58%

Section: Methodsmentioning

confidence: 99%

Maintenance of liver glycogen during long‐term fasting preserves energy state in mice

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…The HVAN has long been implicated in transmitting liver derived signals to the hindbrain to regulate feeding behavior 26,27 . Early work established that hepatic portal infusions of glucose, amino acids, and lipids suppress food intake 28–31 , while more recent studies support that carbohydrate signals originating from the liver regulate feeding behavior through HVAN dependent mechanisms 32,33 . Peripheral satiation factors including glucagon like peptide-1 (GLP-1), cholecystokinin (CCK), lipids, and leptin all reduce food intake dependent upon increasing gastric and hepatic vagal branch afferent firing, while the orexigenic hormone ghrelin suppresses vagal afferent tone 29,34–38 .…”

Section: Discussionmentioning

confidence: 99%

A Critical Role of Hepatic GABA in The Metabolic Dysfunction and Hyperphagia of Obesity

Geisler

Ghimire

Bruggink

et al. 2020

Preprint

View full text Add to dashboard Cite

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) and associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABAtransaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia, and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemiceuglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, HOMA-IR, T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.However, in the liver, GABA-T mediates GABA synthesis 12 . We have proposed that hepatic lipids activate reversed GABA shunt activity in hepatocytes, and that hepatic GABA and glucose production are metabolically linked ). It remains completely untested whether manipulating this GABA shunt can prevent hepatic steatosis derived metabolic disease. Thus, GABA-T represents a promising target to decrease hyperinsulinemia and insulin resistance by limiting hepatic GABA production. Accordingly, in the current manuscript, we employed two novel models to limit hepatic GABA production: 1) pharmacologic inhibition of GABA-T activity, and 2) antisense oligonucleotide (ASO) mediated knockdown of hepatic specific GABA-T expression. Using these models for the first time we assessed systemic glucose homeostasis to strengthen the causative role between hepatic GABA production and hyperinsulinemia / insulin resistance. We also assessed food intake and energy expenditure to understand the role of hepatic GABA production in the dysregulation of energy homeostasis in obesity. Results GABA-Transaminase Inhibition Improves Glucose Homeostasis in ObesityTo directly assess the effect of GABA-T in obesity-induced metabolic dysfunction we treated high fat diet-induced obese mice with one of two irreversible GABA-T inhibitors, ethanolamine-Osulphate (EOS) or vigabatrin (8 mg/day). Both reduce hepatic GABA-T activity by over 90% within two days 13 . Through 5 days of treatment, body weight remained similar among EOS, vigabatrin, and saline injected mice (Fig. 1A). Four days of EOS or vigabatrin treatment decreased serum insulin and glucose concentrations and increased the glucose:insulin ratio relative to pre-treatment ( Figs. 1B-1D). Two-weeks washout from EOS or vigabatrin resulted in a return of serum insulin and the glucose:insulin ratio to pretreatment levels (Figs. 1B-1D). EOS treatment (5 days) decreased serum glucagon relat...

show abstract

“…The liver plays an important role in normalizing blood glucose by converting glucose into hepatic glycogen . In contrast to insulin, the action of hepatic glucagon is rapid and short‐lived.…”

Section: Discussionmentioning

confidence: 99%

Melatonin attenuates smoking‐induced hyperglycemia via preserving insulin secretion and hepatic glycogen synthesis in rats

Zhao

et al. 2018

Journal of Pineal Research

View full text Add to dashboard Cite

Epidemiology survey indicated that cigarette smoking is a risk factor of diabetes. However, the precise mechanisms remain to be clarified. In this study, we found that smoking caused metabolic malfunctions on pancreas and liver in experimental animal model. These were indicated by hyperglycemia, increased serum hemoglobin A1c level and decreased insulin secretion, inhibition of liver glycogen synthase (LGS), and hepatic glycogen synthesis. Mechanistic studies revealed that all these alterations were caused by the inflammatory reaction and reactive oxygen species (ROS) induced by the smoking. Melatonin treatment significantly preserved the functions of both pancreas and liver by reducing β cell apoptosis, CD68‐cell infiltration, ROS production, and caspase‐3 expression. The siRNA‐knockdown model identified that the protective effects of melatonin were mediated by melatonin receptor‐2 (MT2). This study uncovered potentially underlying mechanisms related to the association between smoking and diabetes. In addition, it is, for first time, to report that melatonin effectively protects against smoking‐induced glucose metabolic alterations and the signal transduction pathway of melatonin is mainly mediated by its MT2 receptor. These observations provide solid evidence for the clinically use of melatonin to reduce smoking‐related diabetes, and the therapeutic regimens are absent currently.

show abstract

Effects of hepatic glycogen on food intake and glucose homeostasis are mediated by the vagus nerve in mice

Abstract: Our results demonstrate that the regulation of food intake and glucose homeostasis by liver glycogen is dependent on the hepatic branch of the vagus nerve.

Cited by 35 publications

References 44 publications

Maintenance of liver glycogen during long‐term fasting preserves energy state in mice

Maintenance of liver glycogen during long‐term fasting preserves energy state in mice

A Critical Role of Hepatic GABA in The Metabolic Dysfunction and Hyperphagia of Obesity

Melatonin attenuates smoking‐induced hyperglycemia via preserving insulin secretion and hepatic glycogen synthesis in rats

Contact Info

Product

Resources

About