CPT1α over-expression increases long-chain fatty acid oxidation and reduces cell viability with incremental palmitic acid concentration in 293T cells

Sousa, Ulrike L. Jambor de; Koss, Michael D.; Fillies, Marion; Gahl, Anja; Scheeder, M. R. L.; Cardoso, M. Cristina; Leonhardt, Heinrich; Geary, Nori; Langhans, Wolfgang; Leonhardt, M.

doi:10.1016/j.bbrc.2005.10.016

Cited by 24 publications

(15 citation statements)

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“…UCP2 is widely expressed in tissues and likely associated with the control of reactive oxygen species production by mitochondria, regulation of ATP synthesis, and fatty acid oxidation [30]. CPT1α is the rate-limiting enzyme carnitine palmitoyl-transferase, which regulates fatty acid oxidation [31] and is regulated by PGC1α. Hadhb is the mitochondrial trifunctional protein with a multienzyme complex of the fatty acid β-oxidation cycle [32].…”

Section: Discussionmentioning

confidence: 99%

Effects and Action Mechanisms of Berberine and Rhizoma coptidis on Gut Microbes and Obesity in High-Fat Diet-Fed C57BL/6J Mice

et al. 2011

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Gut microbes play important roles in regulating fat storage and metabolism. Rhizoma coptidis (RC) and its main active compound, berberine, have either antimicrobial or anti-obesity activities. In the present study, we hypothesize that RC exerts anti-obesity effects that are likely mediated by mechanisms of regulating gut microbes and berberine may be a key compound of RC. Gut microbes and glucose and lipid metabolism in high-fat diet-fed C57BL/6J (HFD) mice in vivo are investigated after RC and berberine treatments. The results show that RC (200 mg/kg) and berberine (200 mg/kg) significantly lower both body and visceral adipose weights, and reduce blood glucose and lipid levels, and decrease degradation of dietary polysaccharides in HFD mice. Both RC and berberine significantly reduce the proportions of fecal Firmicutes and Bacteroidetes to total bacteria in HFD mice. In the trial ex vivo, both RC and berberine significantly inhibit the growth of gut bacteria under aerobic and anaerobic conditions. In in vitro trials, both RC and berberine significantly inhibit the growth of Lactobacillus (a classical type of Firmicutes) under anaerobic conditions. Furthermore, both RC and berberine significantly increase fasting-induced adipose factor (Fiaf, a key protein negatively regulated by intestinal microbes) expressions in either intestinal or visceral adipose tissues. Both RC and berberine significantly increase mRNA expressions of AMPK, PGC1α, UCP2, CPT1α, and Hadhb related to mitochondrial energy metabolism, which may be driven by increased Fiaf expression. These results firstly suggest that antimicrobial activities of RC and berberine may result in decreasing degradation of dietary polysaccharides, lowering potential calorie intake, and then systemically activating Fiaf protein and related gene expressions of mitochondrial energy metabolism in visceral adipose tissues. Taken together, these action mechanisms may contribute to significant anti-obesity effects. Findings in the present study also indicate that pharmacological regulation on gut microbes can develop an anti-obesity strategy.

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Section: Discussionmentioning

confidence: 99%

Effects and Action Mechanisms of Berberine and Rhizoma coptidis on Gut Microbes and Obesity in High-Fat Diet-Fed C57BL/6J Mice

et al. 2011

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“…CPT1A is allosterically inhibited by malonyl-CoA, a metabolite generated during de novo lipogenesis (7,10). Transfection of human embryonic 293T kidney cells with the CPT1A cDNA increased the capacity of these cells to oxidize long-chain fatty acids (22). Moreover, adenovirus-mediated expression of a mutated form of CPT1A, CPT1mt, which is constitutively active but insensitive to inhibition by malonylCoA (35), increased mitochondrial FAO in cultured rat hepatocytes (1) and C2C12 muscle cells (17).…”

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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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“…One of these is the stimulation of carnitine palmitoyl-transferase-1 (CPT-1) (2,29,39). Increased CPT-1 activity stimulates fatty acid oxidation (FAO; 19), and several findings indicate that inhibition of peripheral FAO stimulates eating (11,24,36). There are some reports that administration of CPT-1 inhibitors into the central nervous system decreases food intake or body weight (31,33).…”

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Intraperitoneal injections of low doses of C75 elicit a behaviorally specific and vagal afferent-independent inhibition of eating in rats

Mansouri¹,

Moran²,

Ronnett³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Central and intraperitoneal C75, an inhibitor of fatty acid synthase and stimulator of carnitine palmitoyl-transferase-1, inhibits eating in mice and rats. Mechanisms involved in feeding inhibition after central C75 have been identified, but little is yet known about how systemic C75 might inhibit eating. One issue is whether intraperitoneal C75 reduces food intake in rats by influencing normal physiological controls of food intake or acts nonselectively, for example by eliciting illness or aversion. Another issue relates to whether intraperitoneal C75 acts centrally or, similar to some other peripheral metabolic controls of eating, activates abdominal vagal afferents to inhibit eating. To further address these questions, we investigated the effects of intraperitoneal C75 on spontaneous meal patterns and the formation of conditioned taste aversion (CTA). We also tested whether the eating inhibitory effect of intraperitoneal C75 is vagally mediated by testing rats after either total subdiaphragmatic vagotomy (TVX) or selective subdiaphragmatic vagal deafferentations (SDA). Intraperitoneal injection of 3.2 and 7.5 mg/kg of C75 significantly reduced food intake 3, 12, and 24 h after injection by reducing the number of meals without affecting meal size, whereas 15 mg/kg of C75 reduced both meal number and meal size. The two smaller doses of C75 failed to induce a CTA, but 15 mg/kg C75 did. The eating inhibitory effect of C75 was not diminished in either TVX or SDA rats. We conclude that intraperitoneal injections of low doses of C75 inhibit eating in a behaviorally specific manner and that this effect does not require abdominal vagal afferents.

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CPT1α over-expression increases long-chain fatty acid oxidation and reduces cell viability with incremental palmitic acid concentration in 293T cells

Cited by 24 publications

References 24 publications

Effects and Action Mechanisms of Berberine and Rhizoma coptidis on Gut Microbes and Obesity in High-Fat Diet-Fed C57BL/6J Mice

Effects and Action Mechanisms of Berberine and Rhizoma coptidis on Gut Microbes and Obesity in High-Fat Diet-Fed C57BL/6J Mice

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

Intraperitoneal injections of low doses of C75 elicit a behaviorally specific and vagal afferent-independent inhibition of eating in rats

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