The Hepatic Vagus Mediates Fat-Induced Inhibition of Diabetic Hyperphagia

Fleur, Susanne E. la; Hong, Ji Man; Manalo, Sotara; Friedman, Mark I.; Dallman, Mary F.

doi:10.2337/diabetes.52.9.2321

Cited by 60 publications

(55 citation statements)

References 51 publications

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“…Furthermore, streptozotocin-induced hyperphagia was reportedly reversed by hepatic expression of protein phosphatase-1 (29), suggesting that altering hepatic metabolism modulates appetite. Vagal pathways from the liver to the brain mediate the fat-induced changes in hypothalamic neuropeptides and feeding behavior in diabetic rats (30). Taken together with these observations, through appetite modulation, the liver also holds promise as a target for treatment of diabetes with obesity.…”

Section: Discussionmentioning

confidence: 79%

Dissipating Excess Energy Stored in the Liver Is a Potential Treatment Strategy for Diabetes Associated With Obesity

et al. 2005

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For examining whether dissipating excess energy in the liver is a possible therapeutic approach to high-fat diet-induced metabolic disorders, uncoupling protein-1 (UCP1) was expressed in murine liver using adenoviral vectors in mice with high-fat diet-induced diabetes and obesity, and in standard diet-fed lean mice. Once diabetes with obesity developed, hepatic UCP1 expression increased energy expenditure, decreased body weight, and reduced fat in the liver and adipose tissues, resulting in markedly improved insulin resistance and, thus, diabetes and dyslipidemia. Decreased expressions of enzymes for lipid synthesis and glucose production and activation of AMP-activated kinase in the liver seem to contribute to these improvements. Hepatic UCP1 expression also reversed high-fat diet-induced hyperphagia and hypothalamic leptin resistance, as well as insulin resistance in muscle. In contrast, intriguingly, in standard diet-fed lean mice, hepatic UCP1 expression did not significantly affect energy expenditure or hepatic ATP contents. Furthermore, no alterations in blood glucose levels, body weight, or adiposity were observed. These findings suggest that ectopic UCP1 in the liver dissipates surplus energy without affecting required energy and exerts minimal metabolic effects in lean mice. Thus, enhanced UCP expression in the liver is a new potential therapeutic target for the metabolic syndrome. Diabetes 54:322-332, 2005 A n explosive increase in the number of diabetic patients, which has become a major public health concern in most industrialized countries in recent decades (1), is mainly the result of excess energy intake and physical inactivity. When food intake chronically exceeds metabolic needs, efficient metabolism causes excess energy storage and results in obesity, a common condition associated with diabetes, hyperlipidemia, and premature heart disease. Excess energy in cells lowers the response to insulin, namely insulin resistance. However, the major treatment modalities for diabetes, including insulin injection and oral sulfonylureas, aim at lowering blood glucose levels by driving glucose into cells in peripheral tissues such as muscle and fat. This further exacerbates insulin resistance when energy intake is in excess, resulting in a vicious cycle. Therefore, novel therapies that promote increased energy expenditure are needed.Inefficient metabolism, such as the generation of heat instead of ATP, is a potential treatment strategy for type 2 diabetes associated with obesity. Uncoupling proteins (UCPs) were discovered members of the mitochondrial inner membrane carrier family. These proteins leak protons into the mitochondrial matrix, dissipating energy as heat rather than allowing it to be captured in ATP (2). UCP1 (thermogenin) was originally identified in brown adipose tissue and demonstrated to mediate nonshivering thermogenesis. UCP1 plays an important role in mediating cold exposure-induced thermogenesis (3) and is also a likely regulator of diet-induced thermogenesis (4).Several laboratories have r...

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Section: Discussionmentioning

confidence: 79%

Dissipating Excess Energy Stored in the Liver Is a Potential Treatment Strategy for Diabetes Associated With Obesity

et al. 2005

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“…27 Furthermore, we showed that in diabetic rats, the hepatic vagus mediates diet-induced changes in expression of POMC and NPY mRNA. 12,13 These findings suggest that, at least in diabetic rats, the afferent neural input from the liver/intestine contributes to the response of the melanocortin and NPY system to a fat diet. Indeed, the alterations in POMC mRNA levels owing to HF or HFHS choice diets are prevented by hepatic vagotomy; however, alterations in NPY mRNA levels when fed HF or HFHS choice diets were not.…”

Section: Discussionmentioning

confidence: 91%

“…through the hepatic vagal (HV) nerve). 12,13 As we observed differential responses in hypothalamic neuropeptide expression to the diets, we examined hormonal responses and investigated the involvement of neuronal feedback signals in these diet-induced hypothalamic responses.…”

Section: Introductionmentioning

confidence: 99%

A free-choice high-fat high-sugar diet induces changes in arcuate neuropeptide expression that support hyperphagia

et al. 2009

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Objectives:The mechanisms for how saturated fat and sugar-based beverages contribute to human obesity are poorly understood. This paper describes a series of experiments developed to examine the response of hypothalamic neuropeptides to diets rich in sugar and fat, using three different diets: a high-fat high-sugar (HFHS) choice diet with access to chow, saturated fat and a 30% sugar solution; a high-fat (HF) choice diet with access to chow and saturated fat; or to a high-sugar (HS) choice diet with access to chow and a sugar solution. Method: We first studied caloric intake, body weight gain, hormonal alterations and hypothalamic neuropeptide expression when male Wistar rats were subjected to an HFHS choice, an HF choice or an HS choice diet for 1 week. Next, we studied caloric intake and body weight gain when rats were subjected to the choice diets for 5 weeks. Finally, we measured neuropeptide expression in hepatic vagotomized rats subjected to an HFHS choice, an HF choice or an HS choice diet for 1 week. Results: In rats on an HF choice diet, plasma leptin concentrations and proopiomelanocortin (POMC) mRNA increased and neuropeptide Y (NPY) mRNA decreased. Rats on an HFHS choice diet showed identical plasma leptin concentrations as rats on an HF choice diet. However, NPY mRNA increased and POMC mRNA decreased. An HS choice diet for 1 week did not alter hypothalamic neuropeptide expression or plasma leptin concentrations. As hormonal changes did not explain the differences in hypothalamic neuropeptide expression between rats on the choice diets, we addressed whether neuronal feedback signals mediated the hypothalamic neuropeptide response. The POMC mRNA response to different diets depended on an intact innervation of liver and upper intestinal tract. Conclusion: Our data suggest that the specific combination of saturated fat and a 30% sugar solution results in hyperphagiainduced obesity and alters hypothalamic neuropeptide expression, and that the response of the melanocortin system is mediated by the hepatic vagus.

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“…However, LCR rats did demonstrate a greater increase in EI during the acute HFD, evoking a greater 3-day weight gain, increased adiposity, and a twofold higher EB in the LCR vs. HCR. Previous findings show that increased EI on a HFD is due to a predisposition to store dietary calories in adipose and decreased whole body (6) and liver-specific FAO (7), resulting in liver-derived afferent signals to increase food intake (21). Therefore, we posit that the phenotype of the low aerobic capacity rat (increased trafficking of fatty acids to adipose and reduced whole body and hepatic fatty acid oxidation) may drive subsequent elevated acute EI in a feed-forward process that increases EB and worsens steatosis outcomes.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic aerobic capacity impacts susceptibility to acute high-fat diet-induced hepatic steatosis

Morris¹,

Jackman

Johnson

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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PS, Thyfault JP. Intrinsic aerobic capacity impacts susceptibility to acute high-fat diet-induced hepatic steatosis. Am J Physiol Endocrinol Metab 307: E355-E364, 2014. First published June 24, 2014; doi:10.1152/ajpendo.00093.2014.-Aerobic capacity/fitness significantly impacts susceptibility for fatty liver and diabetes, but the mechanisms remain unknown. Herein, we utilized rats selectively bred for high (HCR) and low (LCR) intrinsic aerobic capacity to examine the mechanisms by which aerobic capacity impacts metabolic vulnerability for fatty liver following a 3-day high-fat diet (HFD). Indirect calorimetry assessment of energy metabolism combined with radiolabeled dietary food was employed to examine systemic metabolism in combination with ex vivo measurements of hepatic lipid oxidation. The LCR, but not HCR, displayed increased hepatic lipid accumulation in response to the HFD despite both groups increasing energy intake. However, LCR rats had a greater increase in energy intake and demonstrated greater daily weight gain and percent body fat due to HFD compared with HCR. Additionally, total energy expenditure was higher in the larger LCR. However, controlling for the difference in body weight, the LCR has lower resting energy expenditure compared with HCR. Importantly, respiratory quotient was significantly higher during the HFD in the LCR compared with HCR, suggesting reduced whole body lipid utilization in the LCR. This was confirmed by the observed lower whole body dietary fatty acid oxidation in LCR compared with HCR. Furthermore, LCR liver homogenate and isolated mitochondria showed lower complete fatty acid oxidation compared with HCR. We conclude that rats bred for low intrinsic aerobic capacity show greater susceptibility for dietary-induced hepatic steatosis, which is associated with a lower energy expenditure and reduced whole body and hepatic mitochondrial lipid oxidation. fatty liver; energy intake; fitness; obesity; energy expenditure LOW AEROBIC CAPACITY OR FITNESS is a powerful predictor of cardiovascular and all-cause mortality independent of other risk factors, including smoking, obesity, previous cardiovascular disease, and diabetes (18,19). Importantly, improving fitness also significantly increases survival in previously low-fit individuals (19). Aerobic capacity is also an independent predictor for the development of the metabolic syndrome and type 2 diabetes (12, 34). Low aerobic capacity is also a powerful predictor of nonalcoholic fatty liver disease (NA-FLD) prevalence (2) and negatively impacts lifestyle-based treatments for NAFLD (16). However, the mechanism(s) linking low aerobic capacity to metabolic disease processes remains unknown. In particular, there are limited data documenting the whole body and liver-specific energy metabolism phenotypes that exist between groups of differing aerobic capacities and how these different phenotypes may modulate susceptibility for NAFLD.NAFLD represents a spectrum of disease initially characterized by steatosis that may progress to hepatic in...

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The Hepatic Vagus Mediates Fat-Induced Inhibition of Diabetic Hyperphagia

Cited by 60 publications

References 51 publications

Dissipating Excess Energy Stored in the Liver Is a Potential Treatment Strategy for Diabetes Associated With Obesity

Dissipating Excess Energy Stored in the Liver Is a Potential Treatment Strategy for Diabetes Associated With Obesity

A free-choice high-fat high-sugar diet induces changes in arcuate neuropeptide expression that support hyperphagia

Intrinsic aerobic capacity impacts susceptibility to acute high-fat diet-induced hepatic steatosis

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