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

Abstract

(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...

Dietary thylakoids reduce visceral fat mass and increase expression of genes involved in intestinal fatty acid oxidation in high-fat fed rats

“…The decrease in RQ appeared during the dark period when animals are active, eat more, and normally tend to utilize more carbohydrates than fat (26). The increase in fat utilization over longer periods of time may, at least in part, explain the decrease in body weight and change in body composition seen both in the present study and in previous studies (11).…”

Kaempferol Improves Cardiolipin and ATP in Hepatic Cells: A Cellular Model Perspective in the Context of Metabolic Dysfunction-Associated Steatotic Liver Disease

“…CPT1A is the rate-limiting enzyme for β-oxidation of long-chain fatty acids, and activation of β-oxidation contributes to ATP production [ 32 ]. The overexpression of CPT1 has been shown to enhance hepatic mitochondrial fatty acid oxidation in mice [ 33 ]. KMP increased the protein expression of CPT1A in parallel with its gene expression in HepG2 cells [ 34 ].…”

Reduced Liver-Specific PGC1a Increases Susceptibility for Short-Term Diet-Induced Weight Gain in Male Mice

“…Further, an inverse relationship between the liver-specific modulation of fatty acid oxidation and mitochondrial energy metabolism [33][34][35][36] or associated secondary changes in liver FAO and mitochondria gene expression has been observed with chronic diet-induced weight gain [37,38]. However, others have observed an increased food intake in mice with increased liver FAO following the overexpression of CPT-1 [39]. Our previous findings suggested that the differences in acute HFHS-induced weight gain, body composition changes, and the regulation of food/energy intake are inversely associated with liver tissue PGC1a expression, fatty acid oxidation, and mitochondrial respiratory capacity [40][41][42].…”