Hepatic and intestinal handling of metabolites during feeding in rats

Langhans, Wolfgang

doi:10.1016/0031-9384(91)90352-o

Cited by 27 publications

(16 citation statements)

References 28 publications

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“…Serum levels of NEFA and ␤-hydroxybutyrate (BHB) were determined using an enzyme-based reaction, measuring the absorbance of the resulting metabolite using Cobas Mira autoanalyzer (Cobas Mira; LaRoche, Basel, Switzerland) (26).…”

Section: Methodsmentioning

confidence: 99%

Enhancing hepatic mitochondrial fatty acid oxidation stimulates eating in food-deprived mice

Mansouri

Pacheco-López

Ramachandran

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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(FAO) has long been implicated in the control of eating. Nevertheless, direct evidence for a causal relationship between changes in hepatic FAO and changes in food intake is still missing. Here we tested whether increasing hepatic FAO via adenovirusmediated expression of a mutated form of the key regulatory enzyme of mitochondrial FAO carnitine palmitoyltransferase 1A (CPT1mt), which is active but insensitive to inhibition by malonyl-CoA, affects eating and metabolism in mice. CPT1mt expression increased hepatocellular CPT1 protein levels. This resulted in an increase in circulating ketone body levels in fasted CPT1mt-expressing mice, suggesting an increase in hepatic FAO. These mice did not show any significant changes in cumulative food intake, energy expenditure, or respiratory quotient after 4-h food deprivation. After 24-h food deprivation, however, the CPT1mt-expressing mice displayed increased food intake. Thus expression of CPT1mt in the liver increases hepatic FAO capacity, but does not inhibit eating. Rather, it may even stimulate eating after prolonged food deprivation. These data do not support the hypothesis that an increase in hepatic FAO decreases food intake. energy homeostasis; carnitine palmitoyltransferase 1a; food intake; metabolic control of eating; liver BECAUSE FOOD is the only source of metabolic fuels, it is reasonable to assume that feedback from metabolism contributes to the control of eating, allowing for the maintenance of a balance between the amount of calories spent and ingested (52, 53). The nervous system continuously monitors metabolism to assess the availability of energy-providing fuels such as fatty acids and glucose and to control energy intake and expenditure accordingly. Despite open questions concerning its physiological relevance, the eating-stimulatory effect of inhibitors of glucose utilization or fatty acid oxidation (FAO) is generally considered evidence for the existence of a metabolic control of eating (12,27,43). FAO inhibitors such as mercaptoacetate (MA, an inhibitor of acyl-CoA dehydrogenases) (45) and etomoxir or methyl-palmoxirate (inhibitors of the carnitine palmitoyltransferase-1, CPT1) (13,14,19) reliably stimulate eating in laboratory mice (9, 51), rats (5, 19), and humans (18). The eating-stimulatory effect of MA was associated with a decline in circulating ketone bodies and an increase in nonesterified fatty acids (NEFA), indicating an inhibition of FAO (5, 45). Moreover, FAO inhibitors require intact abdominal vagal afferents to stimulate eating (6,20,29,44), suggesting that they act in the abdominal cavity to do so. Given the major role of the liver in FAO and ketogenesis (38), the eating-stimulatory effect of FAO inhibitors was hypothesized to originate in the liver, with changes in hepatocyte ADP-to-ATP ratio and membrane potential connecting hepatocyte FAO to vagal afferent activity (4,19,27). So far, however, all these findings were correlative, and there is no direct evidence supporting the hypothesis that the liver is the organ where the brai...

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Section: Methodsmentioning

confidence: 99%

Enhancing hepatic mitochondrial fatty acid oxidation stimulates eating in food-deprived mice

Mansouri

Pacheco-López

Ramachandran

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The serum was transferred into Cobas-Mira analyzer cups and stored at 4°C until analysis (see below) later on the same day. Fasting and postprandial serum TAG, plasma free glycerol, nonesterifi ed fatty acid (NEFA), and ␤ -hydroxybutyrate (BHB) concentrations were measured using standard colorimetric and enzymatic methods adapted for the Cobas MIRA® autoanalyzer (Hoffman LaRoche) ( 25 ).…”

Section: Blood Lipid Analysesmentioning

confidence: 99%

Diacylglycerol acyltransferase-1 inhibition enhances intestinal fatty acid oxidation and reduces energy intake in rats

Schober

Arnold

Birtles

et al. 2013

Journal of Lipid Research

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( 1, 2 ). Often an overconsumption of energy-dense, fat-rich food leads to excessive triacylglycerol (TAG) accumulation in adipose and nonadipose tissue. This can result in insulin resistance and nonalcoholic fatty liver disease, emphasizing the need for pharmacotherapeutic approaches that are effective when a high-fat diet (HFD) is consumed ( 3 ).In the small intestine dietary TAGs are hydrolyzed to 2-monoacylglycerols (MAGs) and fatty acids (FAs) that are absorbed . Specifi c binding proteins in the enterocytes shuttle MAG and FFA to the endoplasmic reticulum for reesterifi cation. This involves the acylation from MAG to sn -1,2-diacylglycerol (DAG) by MAG acyltransferase and the acylation from DAG to TAG catalyzed by acyl CoA:diacylglycerol acyltransferase-1 (DGAT-1) (EC 2.3.1.20 ), the rate-limiting step in TAG synthesis ( 4 ). This MAG pathway is important after eating, when intestinal MAG levels are high ( 5 ). DGAT-1 is one of two known DGAT enzymes ( 6 ) in tissues associated with TAG synthesis, including the small intestine ( 6, 7 ), where DGAT-1 is involved in fat absorption, lipoprotein assembly, and regulation of plasma TAG concentrations ( 7 ). DGAT-1 knockout (dgat-1 Obesity is a global epidemic and a major risk factor for type 2 diabetes, hypertension, cardiovascular disease, and other ailments. The development of obesity is multifactorial 28 February 2013. Published, JLR Papers in Press, February 28, 2013 DOI 10.1194 Diacylglycerol acyltransferase-1 inhibition enhances intestinal fatty acid oxidation and reduces energy intake in rats Abbreviations: AMPK ␣ , AMP-activated protein kinase-␣ ; ASP, acid soluble products; AUC, area under the curve; BHB, ␤ -hydroxybutyrate; BT, body temperature; BW, body weight; CFA, conditioned fl avor avoidance; CPT-1, carnitine palmitoyltransferase-1; DAG, sn -1,2-diacylglycerol; DGAT-1, acyl-CoA:diacylglycerol acyltransferase-1; DGAT-1i, diacylglycerol acyltransferase-1 inhibitor; dgat-1 Ϫ / Ϫ This work was supported by Swiss National Science Foundation Grant 31_130665 (W.L.). Manuscript received 19 December 2012 and in revised form

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“…In the dog, hepatic glycogen stores are high after 18 h of fasting (11), and the liver is a net E293 producer of lactate, a sign of being in the fed or very early fasted state (6). In contrast, hepatic glycogen reserves in the rat are markedly depleted after an overnight fast, and the liver is a net consumer of lactate (9,17,30,42). Thus an overnight fast in the dog is unlikely to blunt the HISS response nearly as much as it would in the rat.…”

Section: Arterial Blood Concentrations Net Hepatic and Renal Uptakmentioning

confidence: 99%

Effect of hepatic denervation on peripheral insulin sensitivity in conscious dogs

Moore¹,

Satake²,

Baranowski

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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. Effect of hepatic denervation on peripheral insulin sensitivity in conscious dogs. Am J Physiol Endocrinol Metab 282: E286-E296, 2002; 10.1152/ajpendo.00201. 2001.-We tested the hypothesis that the loss of hepatic nerves decreases peripheral insulin sensitivity. Surgical hepatic denervation (DN) was performed in 22 dogs ϳ16 days before study; 7 dogs (Sham-Sal) had a sham procedure. A euglycemic hyperinsulinemic (1 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ; arterial insulin 35 Ϯ 1 U/ml in all dogs) clamp was performed in conscious dogs. From 0 to 90 min of the clamp, all dogs received the same treatment; then the DN dogs were divided into three groups. From 90 to 180 min, DN-PeA (n ϭ 7) and DN-PoA (n ϭ 7) groups received acetylcholine 2.5 g ⅐ kg Ϫ1 ⅐ min Ϫ1 via peripheral or portal vein, respectively, and DN-Sal (n ϭ 8) received no acetylcholine. During 150-180 min, the Sham-Sal, DN-Sal, DN-PeA, and DN-PoA groups exhibited glucose infusion rates of 12.4 Ϯ 0.8, 9.3 Ϯ 0.8 (P Ͻ 0.05 vs. Sham-Sal), 9.1 Ϯ 0.1 (P Ͻ 0.05 vs. ShamSal), and 12.7 Ϯ 1.6 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ; nonhepatic glucose uptakes of 11.5 Ϯ 0.9, 8.9 Ϯ 0.7 (P Ͻ 0.05 vs. Sham-Sal), 8.6 Ϯ 0.9 (P Ͻ 0.05 vs. Sham-Sal), and 11.9 Ϯ 1.7 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ; net hindlimb glucose uptakes of 18.4 Ϯ 2.1, 13.7 Ϯ 1.1 (P Ͻ 0.05 vs. Sham-Sal), 17.5 Ϯ 1.9, and 16.7 Ϯ 3.2 mg/min; and glucose utilization rates of 14.4 Ϯ 1.4, 10.4 Ϯ 0.8 (P Ͻ 0.05 vs. Sham-Sal), 9.8 Ϯ 0.9 (P Ͻ 0.05 vs. Sham-Sal), and 13.6 Ϯ 1.8 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 , respectively. DN caused peripheral insulin resistance, and intraportal but not peripheral acetylcholine restored insulin sensitivity. hepatic nerves; acetylcholine HEPATIC DENERVATION has been reported to result in peripheral insulin resistance in both rats and cats (49-51). The insulin resistance, which can be localized primarily to skeletal muscle (50), is reversible by intraportal, but not peripheral, infusion of acetylcholine (49) or a nitric oxide donor (35). This has led Lautt (19) to propose that insulin stimulates a hepatic parasympathetic reflex. According to this hypothesis, the reflex involves the release of acetylcholine, which binds to muscarinic receptors and stimulates the production of nitric oxide within the liver. As a result, the liver releases a humoral factor termed the hepatic insulinsensitizing substance, or HISS, that sensitizes skeletal muscle to insulin or has a direct insulin-like action (19). Although this is a very intriguing suggestion, the studies upon which it is based were performed in acutely denervated anesthetized animals under nonsteady-state conditions with the use of bolus injections of insulin. Therefore, the relevance of these findings to stable, conscious animals receiving physiological amounts of insulin remains to be established.We designed the current studies to test the hypothesis that loss of the hepatic nerves would impair peripheral glucose disposal under carefully controlled hormonal conditions in a physiological model. Specifically, we examined the response of conscious dogs ϳ16 days after hepatic denervation, u...

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Hepatic and intestinal handling of metabolites during feeding in rats

Cited by 27 publications

References 28 publications

Enhancing hepatic mitochondrial fatty acid oxidation stimulates eating in food-deprived mice

Enhancing hepatic mitochondrial fatty acid oxidation stimulates eating in food-deprived mice

Diacylglycerol acyltransferase-1 inhibition enhances intestinal fatty acid oxidation and reduces energy intake in rats

Effect of hepatic denervation on peripheral insulin sensitivity in conscious dogs

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