Glycogen shortage during fasting triggers liver–brain–adipose neurocircuitry to facilitate fat utilization

Izumida, Yoshihiko; Yahagi, Naoya; Takeuchi, Yoshinori; Nishi, Masatoshi; Shikama, Akito; Takarada, Ayako; Masuda, Yukari; Kubota, Midori; Matsuzaka, Takashi; Nakagawa, Yoshimi; Ikoma, Yoko; Itaka, Keiji; Kataoka, Kazunori; Shioda, Seiji; Niijima, Akira; Yamada, Tetsuya; Katagiri, Hideki; Nagai, Ryozo; Yamada, Nobuhiro; Kadowaki, Takashi; Shimano, Hitoshi

doi:10.1038/ncomms3316

Cited by 91 publications

(68 citation statements)

References 16 publications

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“…We therefore conclude that neither changes in de novo lipogenesis nor changes in lipid oxidation contributed to the decrease in hepatic lipid content in the HFD-fed PTG OE mouse group. A recent study revealed that glycogen shortage in the liver triggers the liver-brain-adipose tissue neural axis independently of glucose and insulin/glucagon levels, thus playing a key role in switching the fuel source from glycogen to triglycerides under prolonged fasting conditions (48). The present results support these observations because overnight-fasted PTG OE mice had higher glycogen levels than control mice.…”

Section: Discussionsupporting

confidence: 82%

Liver Glycogen Reduces Food Intake and Attenuates Obesity in a High-Fat Diet–Fed Mouse Model

et al. 2014

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We generated mice that overexpress protein targeting to glycogen (PTG) in the liver (PTG OE ), which results in an increase in liver glycogen. When fed a high-fat diet (HFD), these animals reduced their food intake. The resulting effect was a lower body weight, decreased fat mass, and reduced leptin levels. Furthermore, PTG overexpression reversed the glucose intolerance and hyperinsulinemia caused by the HFD and protected against HFD-induced hepatic steatosis. Of note, when fed an HFD, PTG OE mice did not show the decrease in hepatic ATP content observed in control animals and had lower expression of neuropeptide Y and higher expression of proopiomelanocortin in the hypothalamus. Additionally, after an overnight fast, PTG OE animals presented high liver glycogen content, lower liver triacylglycerol content, and lower serum concentrations of fatty acids and b-hydroxybutyrate than control mice, regardless of whether they were fed an HFD or a standard diet. In conclusion, liver glycogen accumulation caused a reduced food intake, protected against the deleterious effects of an HFD, and diminished the metabolic impact of fasting. Therefore, we propose that hepatic glycogen content be considered a potential target for the pharmacological manipulation of diabetes and obesity.Liver glycogen acts as an energy store in times of nutritional sufficiency for use in times of need. The metabolism of this polysaccharide in the liver is controlled by the activities of two key enzymes: glycogen synthase (GS) and glycogen phosphorylase (GP) (1). GS is phosphorylated at multiple sites, which induces its inactivation, whereas GP is activated by phosphorylation at a single site. Both enzymes are also regulated allosterically (2,3).Glycogen-targeting subunits bind to glycogen and protein phosphatase 1 (PP1) and facilitate the dephosphorylation of GS and GP, thus activating the former and inactivating the latter. Six genes encode glycogen-targeting subunits (4). Among these, protein targeting to glycogen (PTG) (PPP1R3C or PPP1R5), which is expressed in many tissues, has been shown to control glycogen stores in various animal models (5-7).Adenoviral PTG overexpression in the liver of normal rats increases glycogen and improves glucose tolerance without perturbing lipid metabolism (8). In a diabeticfocused approach, Yang and Newgard (9) showed that adenoviral expression of PTG in the liver of STZ-diabetic rats increased glycogen content and reversed hyperglycemia and hyperphagia. Through a different approach, we reported that hepatic adenoviral expression of an active form of liver GS (LGS), which also increases glycogen content, in STZ-diabetic rats reduced food intake and hyperglycemia (10).Russek (11) was the first to propose a hepatostatic theory of food intake, which was further redefined as a glycogenostatic model by Flatt (12). This model predicts that individuals consume food to a level that maintains glycogen levels in the body (12). In fact, many lines of experimental evidence establish a correlation between the size of liver ...

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Section: Discussionsupporting

confidence: 82%

Liver Glycogen Reduces Food Intake and Attenuates Obesity in a High-Fat Diet–Fed Mouse Model

et al. 2014

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“…In addition, when food is scarce, the liver becomes the storage site for triacylglycerols (TAGs), thus acting as a reservoir of energetic substrates that can be liberated [51]. When the stored TAGs are depleted, the free fatty acids (FFAs) and glycerol released are directly oxidized as an energy source by certain tissues (liver and muscle) [50]. Moreover, adenosine triphosphate can be produced through the oxidation of FFAs, and glycerol can be used as a substrate in gluconeogenesis or lipogenesis Fasting, Cognitive Performance and Exercise [50].…”

Section: Intermittent Fastingmentioning

confidence: 99%

“…IF enhances parasympathetic activity (mediated by the neurotransmitter acetylcholine) in the autonomic neurons that innervate the gut, heart, and arteries, resulting in improved gut motility and reduced heart rate and blood pressure. By depleting glycogen from liver cells, fasting also results in lipolysis [49,50]. In addition, when food is scarce, the liver becomes the storage site for triacylglycerols (TAGs), thus acting as a reservoir of energetic substrates that can be liberated [51].…”

Section: Intermittent Fastingmentioning

confidence: 99%

Effects of Intermittent Fasting, Caloric Restriction, and Ramadan Intermittent Fasting on Cognitive Performance at Rest and During Exercise in Adults

et al. 2015

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The aim of this review was to highlight the potent effects of intermittent fasting on the cognitive performance of athletes at rest and during exercise. Exercise interacts with dietary factors and has a positive effect on brain functioning. Furthermore, physical activity and exercise can favorably influence brain plasticity. Mounting evidence indicates that exercise, in combination with diet, affects the management of energy metabolism and synaptic plasticity by affecting molecular mechanisms through brain-derived neurotrophic factor, an essential neurotrophin that acts at the interface of metabolism and plasticity. The literature has also shown that certain aspects of physical performance and mental health, such as coping and decision-making strategies, can be negatively affected by daylight fasting. However, there are several types of intermittent fasting. These include caloric restriction, which is distinct from fasting and allows subjects to drink water ad libitum while consuming a very low-calorie food intake. Another type is Ramadan intermittent fasting, which is a religious practice of Islam, where healthy adult Muslims do not eat or drink during daylight hours for 1 month. Other religious practices in Islam (Sunna) also encourage Muslims to practice intermittent fasting outside the month of Ramadan. Several cross-sectional and longitudinal studies have shown that intermittent fasting has crucial effects on physical and intellectual performance by affecting various aspects of bodily physiology and biochemistry that could be important for athletic success. Moreover, recent findings revealed that immunological variables are also involved in cognitive functioning and that intermittent fasting might impact the relationship between cytokine expression in the brain and cognitive deficits, including memory deficits.

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“…In order to meet the systemic energy demands during a fast, hormonal signals stimulate adipose tissue to release non-esterified fatty acids (NEFA) into circulation at a rate which exceeds clearance by non-hepatic tissues (Patel et al 2002, Djurhuus et al 2004. Additionally, depression of hepatic glycogen stores during fasting further stimulates adipose tissue lipolysis, indicating that in addition to external hormonal signals, internal liverderived signals regulate systemic energy metabolism and promote lipid mobilization (Izumida et al 2013). To better clear circulating fatty acids, the liver upregulates expression of the hepatic fatty acid transporter Cd36 (Xu et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

156

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Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

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Glycogen shortage during fasting triggers liver–brain–adipose neurocircuitry to facilitate fat utilization

Cited by 91 publications

References 16 publications

Liver Glycogen Reduces Food Intake and Attenuates Obesity in a High-Fat Diet–Fed Mouse Model

Liver Glycogen Reduces Food Intake and Attenuates Obesity in a High-Fat Diet–Fed Mouse Model

Effects of Intermittent Fasting, Caloric Restriction, and Ramadan Intermittent Fasting on Cognitive Performance at Rest and During Exercise in Adults

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

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