Different responses of metallothionein and leptin induced in the mouse by fasting stress

Changes in metallothionein (MT) and leptin under fasting stress were studied. MT content in the liver of mice increased markedly during continuous fasting periods up to 66 h. Hepatic content of MT increased significantly in mice during the first three cycles of alternate daily fasting-feeding, and then the rate of increase gradually decreased with repetition of this cycle. At the end of 10 cycles, the hepatic MT content was still greater in stressed mice than in the control, although the rate of increase decreased. On the other hand, the plasma concentration of leptin decreased dramatically during continuous fasting. The plasma leptin level recovered to the basal level at the end of 10 cycles of fasting-feeding. These data indicate that MT induction was strongly increased, but leptin was scarcely induced under the continuous fasting stress, and that rates of the changes in MT and leptin levels were gradually reduced under the repeated fasting stress, which may result from an inborn tolerance. Fasting presumably causes translocation of zinc from intracellular to extracellular space, from which it is taken into target organs. The increased zinc-bound MT under the continuous fasting may partly result from the need to maintain zinc and protect tissues against oxidative damage.     

Absence of HDL cholesteryl ester uptake in mice via SR-BI impairs an adequate adrenal glucocorticoid-mediated stress response to fasting

Receptor-mediated cholesterol uptake has been suggested to play a role in maintaining the adrenal intracellular free cholesterol pool and the ability to produce hormones. Therefore, in the current study, we evaluated the importance of scavenger receptor class B type I (SR-BI)-mediated cholesteryl ester uptake from HDL for adrenal glucocorticoid hormone synthesis in vivo. No difference was observed in the plasma level of corticosterone between SR-BI-deficient and wild-type mice under ad libitum feeding conditions. Overnight fasting ( approximately 16 h) stimulated the plasma level of corticosterone by 2-fold in wild-type mice. In contrast, no effect of fasting on plasma corticosterone levels was observed in SR-BI-deficient mice, leading to a 44% lower plasma corticosterone level compared with their wild-type littermate controls. In parallel, an almost complete depletion of lipid stores in the adrenal cortex of fasted SR-BI-deficient mice was observed. Plasma adrenocorticotropic hormone levels were increased by 5-fold in fasted SR-BI-deficient mice. SR-BI deficiency induced marked changes in the hepatic expression of the glucocorticoid-responsive genes cholesterol 7alpha-hydroxylase, HMG-CoA synthase, apolipoprotein A-IV, corticosteroid binding globulin, interleukin-6, and tumor necrosis factor-alpha, which coincided with a 42% decreased plasma glucose level under fasting conditions. In conclusion, we show that the absence of adrenal HDL cholesteryl ester uptake in SR-BI-deficient mice impairs the adrenal glucocorticoid-mediated stress response to fasting as a result of adrenal glucocorticoid insufficiency and attenuated liver glucocorticoid receptor signaling, leading to hypoglycemia under fasting conditions.     

Pulmonary responses to acute ozone exposure in fasted mice: effect of leptin administration.

Leptin is a satiety hormone that also has proinflammatory effects, including augmentation of ozone-induced pulmonary inflammation. The purpose of this study was to determine whether reductions in endogenous levels of leptin can attenuate pulmonary responses to ozone. To reduce serum leptin, we fasted mice overnight before ozone exposure. Fasting caused a marked reduction in serum leptin to approximately one-sixth the levels observed in fed mice, and continuous infusion of leptin via Alzet micro-osmotic pumps restored serum leptin to, but not above, fed levels. Ozone exposure (2 ppm for 3 h) caused a significant, approximately 40% increase in pulmonary resistance (P < 0.01) and increased airway responsiveness in fasted but not in fed mice. The increased effect of ozone on pulmonary mechanics and airway responsiveness in fasted mice was not observed when leptin was restored via continuous infusion. Ozone exposure caused pulmonary inflammation, as evident by increases in bronchoalveolar lavage cells, protein, and soluble tumor necrosis factor receptors. There was no effect of fasting status on ozone-induced changes in the bronchoalveolar lavage inflammatory profile, and leptin treatment did not alter these responses. Our results indicate that fasting augments ozone-induced changes in pulmonary mechanics and airway responsiveness in mice. These effects of fasting are the result of declines in serum leptin. The mechanistic basis for this protective effect of leptin in fasted mice remains to be determined but is not related to effects on ozone-induced inflammation.     

Leptin concentrations in plasma and follicular fluid from prepubertal gilts as influenced by fasting, refeeding and insulin.

This study's aim was to examine whether fasting and refeeding would influence leptin levels in both plasma and follicular fluid from prepubertal gilts, and whether insulin affects leptin levels in fasting gilts. In experiment 1, four gilts were fasted for 72 h and then refed. Blood samples were withdrawn during normoalimentation, at the end of fasting, and for 4 h after refeeding. All samples were assayed for leptin; alternate samples were assayed for insulin, glucose and non-esterified fatty acids (NEFA). Fasting caused a decrease in leptin, glucose and insulin levels in plasma, while NEFA concentrations increased. In experiment 2, four gilts were given insulin as a bolus (0.2 IU/kg body weight) after 68 h of fasting. Blood samples were collected every 15 min around insulin administration and were assayed for leptin, insulin and glucose. This experiment shows that insulin administration increases leptin levels during fasting. In experiment 3, gilts were ovariectomized during normal alimentation (n=4), after 48 h of fasting (n=4), and after 48 h of realimentation following 48 h of fasting (n=4). Leptin levels in both plasma and follicular fluid collected after 48 h of fasting were significantly lower than those observed during normoalimentation or refeeding. In conclusion, a transient increase in insulin during fasting is effective in restoring leptin concentrations; in addition, leptin levels in follicular fluid parallel those in plasma.     

Fasting and glucose effects on pituitary leptin expression: is leptin a local signal for nutrient status?

Leptin, a potent anorexigenic hormone, is found in the anterior pituitary (AP). The aim of this study was to determine whether and how pituitary leptin-bearing cells are regulated by nutritional status. Male rats showed 64% reductions in pituitary leptin mRNA 24 hr after fasting, accompanied by significant (30-50%) reductions in growth hormone (GH), prolactin, and luteinizing hormone (LH), and 70-80% reductions in target cells for gonadotropin-releasing hormone or growth hormone-releasing hormone. There was a 2-fold increase in corticotropes. Subsets (22%) of pituitary cells coexpressed leptin and GH, and <5% coexpressed leptin and LH, prolactin, thyroid-stimulating hormone, or adrenocorticotropic hormone. Fasting resulted in significant (55-75%) losses in cells with leptin proteins or mRNA, and GH or LH. To determine whether restoration of serum glucose could rescue leptin, LH, and GH, additional fasted rats were given 10% glucose water for 24 hr. Restoring serum glucose in fasted rats resulted in pituitary cell populations with normal levels of leptin and GH and LH cells. Similarly, LH and GH cells were restored in vitro after populations from fasted rats were treated for as little as 1 hr in 10-100 pg/ml leptin. These correlative changes in pituitary leptin, LH, and GH, coupled with leptin's rapid restoration of GH and LH in vitro, suggest that pituitary leptin may signal nutritional changes. Collectively, the findings suggest that pituitary leptin expression could be coupled to glucose sensors like glucokinase to facilitate rapid responses by the neuroendocrine system to nutritional cues.     

Severe pulmonary hypertension in aging female apolipoprotein E-deficient mice is rescued by estrogen replacement therapy

Corticotropin-releasing factor overexpressing (CRF-OE) male mice showed an inhibited feeding response to a fast, and lower plasma acyl ghrelin and Fos expression in the arcuate nucleus compared to wild-type (WT) mice. We investigated whether hormones and hypothalamic feeding signals are impaired in CRF-OE mice and the influence of sex. Male and female CRF-OE mice and WT littermates (4–6 months old) fed ad libitum or overnight fasted were assessed for body, adrenal glands and perigonadal fat weights, food intake, plasma hormones, blood glucose, and mRNA hypothalamic signals. Under fed conditions, compared to WT, CRF-OE mice have increased adrenal glands and perigonadal fat weight, plasma corticosterone, leptin and insulin, and hypothalamic leptin receptor and decreased plasma acyl ghrelin. Compared to male, female WT mice have lower body and perigonadal fat and plasma leptin but higher adrenal glands weights. CRF-OE mice lost these sex differences except for the adrenals. Male CRF-OE and WT mice did not differ in hypothalamic expression of neuropeptide Y (NPY) and proopiomelanocortin (POMC), while female CRF-OE compared to female WT and male CRF-OE had higher NPY mRNA levels. After fasting, female WT mice lost more body weight and ate more food than male WT, while CRF-OE mice had reduced body weight loss and inhibited food intake without sex difference. In male WT mice, fasting reduced plasma insulin and leptin and increased acyl ghrelin and corticosterone while female WT showed only a rise in corticosterone. In CRF-OE mice, fasting reduced insulin while leptin, acyl ghrelin and corticosterone were unchanged with no sex difference. Fasting blood glucose was higher in CRF-OE with female > male. In WT mice, fasting increased hypothalamic NPY expression in both sexes and decreased POMC only in males, while in CRF-OE mice, NPY did not change, and POMC decreased in males and increased in females. These data indicate that CRF-OE mice have abnormal basal and fasting circulating hormones and hypothalamic feeding-related signals. CRF-OE also abolishes the sex difference in body weight, abdominal fat, and fasting-induced feeding and changes in plasma levels of leptin and acyl ghrelin.     

PPAR alpha-activation results in enhanced carnitine biosynthesis and OCTN2-mediated hepatic carnitine accumulation

In fasted rodents hepatic carnitine concentration increases considerably which is not observed in PPAR alpha-/- mice, indicating that PPAR alpha is involved in carnitine homeostasis. To investigate the mechanisms underlying the PPAR alpha-dependent hepatic carnitine accumulation we measured carnitine biosynthesis enzyme activities, levels of carnitine biosynthesis intermediates, acyl-carnitines and OCTN2 mRNA levels in tissues of untreated, fasted or Wy-14643-treated wild type and PPAR alpha-/- mice. Here we show that both enhancement of carnitine biosynthesis (due to increased gamma-butyrobetaine dioxygenase activity), extra-hepatic gamma-butyrobetaine synthesis and increased hepatic carnitine import (OCTN2 expression) contributes to the increased hepatic carnitine levels after fasting and that these processes are PPAR alpha-dependent.     

Effect of fasting on islet lysosomal enzyme activities and the in vivo insulin response to different secretagogues

The effect of a 24 hr starvation period on islet lysosomal enzyme activities and the in vivo insulin response to glucose, glibenclamide and L-isopropyl-noradrenaline (L-IPNA) was studied in mice. It was observed that fasting induced a significant decrease of islet acid amyloglucosidase activity, whereas the activities of acid phosphatase, beta-N-acetyl-glucosaminidase, and beta-glucuronidase in islet tissue were unaffected by the fasting period studied. Starvation markedly reduced the acute insulin response to a maximal dose of glucose or glibenclamide. However, the insulin response to a maximal dose of L-IPNA was of similar magnitude in both fed and fasted animals. Pretreatment of fasted mice with purified fungal acid amyloglucosidase could restore the impaired insulin response to glucose to the normal level seen in fed mice. It is suggested that islet acid amyloglucosidase activity is of importance for glucose-stimulated insulin secretion, and that reduced levels of islet amyloglucosidase may contribute to the impairment of glucose-induced insulin release seen after fasting.     

Role of IL-6 in the induction of hepatic metallothionein in mice after partial hepatectomy

Metallothioneins (MT) are induced upon partial hepatectomy (PH), possibly mediated by various cytokines. In the present study, we studied cytokine-dependent MT synthesis in partially hepatectomized IL-6 gene knock-out (GKO) mice in the remaining lobe of the liver. We focused on IL-6, TNFalpha and IL-1beta, the major cytokines thought to be involved in MT synthesis. The IL-6 GKO mice and B6J129Sv (wild-type control) mice were subjected to 70% PH or laparotomy. We found that MT was significantly decreased in IL-6 GKO mice, although PH induced hepatic MT in both strains of mice. Laparotomy induced MT in the liver of wild-type mice but not in IL-6 GKO mice. Pretreatment of IL-6 GKO mice with rIL-6 (5 microg/mouse) restored hepatic MT synthesis. Serum IL-6 level in wild-type mice was maximal at 6 h after surgery and decreased thereafter. Serum IL-1beta was the same in both strains of mice. Serum TNFalpha basal level in IL-6 GKO mice was higher than in wild-type mice. PH caused an increase in serum TNFalpha level in both strains of mice, and it was two times higher in IL-6 GKO mice than in wild-type mice at 18 h after surgery. We conclude that IL-6 plays a predominant role in hepatic MT synthesis after PH, but that IL-6 GKO mice still reserve the capacity to synthesize MT by an as yet unidentified mechanism.     

Fasting-induced suppression of LH secretion does not require activation of ATP-sensitive potassium channels

Reproductive hormone secretions are inhibited by fasting and restored by feeding. Metabolic signals mediating these effects include fluctuations in serum glucose, insulin, and leptin. Because ATP-sensitive potassium (K(ATP)) channels mediate glucose sensing and many actions of insulin and leptin in neurons, we assessed their role in suppressing LH secretion during food restriction. Vehicle or a K(ATP) channel blocker, tolbutamide, was infused into the lateral cerebroventricle in ovariectomized mice that were either fed or fasted for 48 h. Tolbutamide infusion resulted in a twofold increase in LH concentrations in both fed and fasted mice compared with both fed and fasted vehicle-treated mice. However, tolbutamide did not reverse the suppression of LH in the majority of fasted animals. In sulfonylurea (SUR)1-null mutant (SUR1(-/-)) mice, which are deficient in K(ATP) channels, and their wild-type (WT) littermates, a 48-h fast was found to reduce serum LH concentrations in both WT and SUR(-/-) mice. The present study demonstrates that 1) blockade of K(ATP) channels elevates LH secretion regardless of energy balance and 2) acute fasting suppresses LH secretion in both SUR1(-/-) and WT mice. These findings support the hypothesis that K(ATP) channels are linked to the regulation of gonadotropin-releasing hormone (GnRH) release but are not obligatory for mediating the effects of fasting on GnRH/LH secretion. Thus it is unlikely that the modulation of K(ATP) channels either as part of the classical glucose-sensing mechanism or as a component of insulin or leptin signaling plays a major role in the suppression of GnRH and LH secretion during food restriction.     

Central infusion of recombinant ovine leptin normalizes plasma insulin and stimulates a novel hypersecretion of luteinizing hormone after short-term fasting in mature beef cows

The present studies tested the hypotheses that short-term fasting would reduce leptin gene expression and circulating concentrations of leptin and insulin in mature, ovariectomized, estradiol-implanted cows and that intracerebroventricular infusions of recombinant ovine leptin (oleptin) would attenuate reductions in insulin concentration and stimulate LH secretion. Ovariectomized cows were assigned to either control (normal fed; n = 6) or fasted (60 h of fasting; n = 7) groups and infused with 200 microg recombinant oleptin three times at hourly intervals on Day 2 (n = 6 per group). Fasting decreased plasma concentrations of insulin (P < 0.01) and leptin (P < 0.04) but, as expected, did not reduce plasma concentrations of glucose or any LH secretion variable. Central infusion of leptin on Day 2 increased (P < 0.01) plasma concentrations of leptin in both control and fasted groups. Concomitantly, leptin treatment increased plasma insulin (P < 0.01) and LH (P < 0.03) concentrations in fasted but not in control cows. Increases in overall mean and baseline concentrations of LH after leptin treatment were the result of an augmentation of the size of LH pulses. The effects of fasting on leptin gene expression and the potential diurnal effects on circulating leptin were examined in a group of cows (n = 12) not treated with leptin. Fasting for 60 h reduced (P < 0.001) leptin gene expression by 30%, and no diurnal effects on circulating leptin were observed. These results indicate that although short-term fasting does not reduce the frequency or amplitude of LH pulses or the concentration of LH in mature cows, this nutritional perturbation clearly sensitizes both the hypothalamic-pituitary axis and endocrine pancreas to exogenous leptin, which in these experiments resulted in heightened secretion of both LH and insulin.     

Recombinant leptin in the hypothalamic response to late fasting

The aim of the current study was to gain further insight into the implication of leptin in the regulation of hypothalamic gene expression during long-term food deprivation with emphasis on phase 3 of fasting (P3, late protein breakdown). Among plasma parameters, glucose, non-esterified fatty acids, and insulin levels tended to be decreased by leptin infusion, whilst corticosterone levels remained unchanged. From Northern blot analysis, NPY, AGRP, and MCH mRNA gene expressions were differentially regulated during prolonged fasting in leptin-perfused rats. In comparison with fed animals, NPY, AGRP, and MCH mRNA levels in P3 rats treated with leptin either remained stable or increased slightly. Regarding anorexigenic peptides (CART and POMC) and prepro-OX, fasting with leptin induced only slight changes in gene expression. Similar data have been obtained in leptin-treated fasted rats at various doses within the physiological range. We conclude that leptin and particularly low levels of plasma leptin can reasonably be considered as a constituent of a signal triggering the fasting-induced enhanced drive for refeeding in P3.     

Dietary carbohydrate level and glucose metabolism in turkey poults.

1. Feeding British United turkeys (BUT) and Nicholas turkeys (NT) diets with varying carbohydrate levels for 24 hr post-hatch resulted in lower hepatic glucose-6-phosphatase activity and higher plasma glucose levels as dietary carbohydrate level was increased. 2. There were no differences between the strains in liver weight or glucose-6-phosphatase activity, but BUT exhibited higher plasma glucose values than did NT at the two highest levels of carbohydrate. Plasma glucose did not differ between strains at the lowest level of carbohydrate or in fasted poults. 3. Blood glucose values were consistently higher in both strains when sampled 1 hr after initial sampling of fasted poults. 4. Both strains were able to maintain the 1 hr blood glucose levels through 24 hr when kept at approximately 37 degrees C. 5. When held at approximately 21 C for the first hour and at approximately 37 degrees C through 24 hr fasted NT were able to maintain the initial blood glucose rise while BUT were not.     

PPARα-activation results in enhanced carnitine biosynthesis and OCTN2-mediated hepatic carnitine accumulation

In fasted rodents hepatic carnitine concentration increases considerably which is not observed in PPARα−/− mice, indicating that PPARα is involved in carnitine homeostasis. To investigate the mechanisms underlying the PPARα-dependent hepatic carnitine accumulation we measured carnitine biosynthesis enzyme activities, levels of carnitine biosynthesis intermediates, acyl-carnitines and OCTN2 mRNA levels in tissues of untreated, fasted or Wy-14643-treated wild type and PPARα−/− mice. Here we show that both enhancement of carnitine biosynthesis (due to increased γ-butyrobetaine dioxygenase activity), extra-hepatic γ-butyrobetaine synthesis and increased hepatic carnitine import (OCTN2 expression) contributes to the increased hepatic carnitine levels after fasting and that these processes are PPARα-dependent.     

Decreased hepatic triglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid-binding protein gene

Liver fatty acid-binding protein (L-Fabp) is an abundant cytosolic lipid-binding protein with broad substrate specificity, expressed in mammalian enterocytes and hepatocytes. We have generated mice with a targeted deletion of the endogenous L-Fabp gene and have characterized their response to alterations in hepatic fatty acid flux following prolonged fasting. Chow-fed L-Fabp-/- mice were indistinguishable from wild-type littermates with regard to growth, serum and tissue lipid profiles, and fatty acid distribution within hepatic complex lipid species. In response to 48-h fasting, however, wild-type mice demonstrated a approximately 10-fold increase in hepatic triglyceride content while L-Fabp-/- mice demonstrated only a 2-fold increase. Hepatic VLDL secretion was decreased in L-Fabp-/- mice suggesting that the decreased accumulation of hepatic triglyceride was not the result of increased secretion. Fatty acid oxidation, as inferred from serum beta-hydroxybutyrate levels, was increased in response to fasting, although the increase in L-Fabp-/- mice was significantly reduced in comparison to wild-type controls, despite comparable induction of PPAR alpha target genes. Studies in primary hepatocytes revealed indistinguishable initial rates of oleate uptake, but longer intervals revealed reduced rates of uptake in fasted L-Fabp-/- mice. Oleate incorporation into cellular triglyceride and diacylglycerol was reduced in L-Fabp-/- mice although incorporation into phospholipid and cholesterol ester was no different than wild-type controls. These data point to an inducible defect in fatty acid utilization in fasted L-Fabp-/- mice that involves targeting of substrate for use in triglyceride metabolism.     

Leptin, gastrointestinal and stress hormones in response to exercise in fasted or fed subjects and before or after blood donation.

Leptin, an ob gene product of adipocytes, plays a key role in the control of food intake and energy expenditure but little is known about leptin response to strenuous exercise in fasted and fed subjects or before and after blood donation. This study was designed to determine the immediate effects of strenuous exercise in healthy volunteers under fasting or fed conditions and before and one day after blood donation (450 ml) on plasma levels of leptin and gut hormones [gastrin, cholecystokinin (CCK), pancreatic polypeptide (PP) and insulin], as well as on "stress" hormones (cortisol, catecholamines and growth hormone. Two groups (A and B) of healthy non-smoking male volunteers were studied. All subjects performed incremental exercise tests until exhaustion (up to maximal oxygen uptake--VO2max), followed by 2 h of rest session. Group A perfomed the tests on a treadmill, while group B on a cycloergometer. In group A, one exercise was performed under fasting conditions and the second following ingestion of a standard liquid meal. In group B, one exercise test was performed as a control test and the second 24 h after blood donation (450 ml). Blood samples were withdrawn 5 min before the start of the test, at the VO2max, and 2 h after finishing the exercise. No significant change in plasma teptin were observed both immediately and 2 h after the exercise in fasted subjects, but after the meal the plasma leptin at VO2max and 2 h after the test was significantly higher, while after blood donation was significantly reduced. The postprandial rise in plasma leptin was accompanied by a marked increment in gut hormones; gastrin, CCK and PP and stress hormones such as norepinephrine, cortisol and GH. These hormonal changes could contribute to the postprandial rise in plasma leptin concentrations, while the fall of leptin after blood donation could be attributed to the inadequate response of stress hormones and autonomic nervous system to exhausting exercise. We conclude that strenuous physical exercise; 1) fails to affect plasma leptin level but when performed after meal but not after blood withdrawal it results in an increase and fall in plasma leptin, and 2) the release of gut hormones (gastrin, CCK and PP) and stress hormones (norepinephrine, cortisol, GH) increase immediately after exercise independently of feeding or blood donation and 3) following blood donation the strenuous exercise resulted in a marked reduction in the plasma leptin, cortisol and GH concentrations, possibly due to the impairment in the autonomic nervous control of these hormones.     

Leptin response to short-term fasting in sympathectomized men: role of the SNS

We studied plasma leptin levels in six people with high-lesion spinal cord injury [SCI; body mass index (BMI) 25.9 +/- 1.5 kg/m(2), age 37 +/- 3.0 yr] and six able-bodied (AB) controls (BMI 29.1 +/- 1.9 kg/m(2), age 35 +/- 3.5 yr) before and after 12, 24, and 36 h of fasting. The plasma leptin levels significantly decreased during 36 h fasting by 48.8 +/- 4.5% (pre: 11.3 +/- 2.3, post: 6.2 +/- 1.5 ng/ml) and 38.6 +/- 7.9% (pre: 7.6 +/- 5.0, post: 4.2 +/- 1.0 ng/ml) in SCI and AB, respectively. Plasma leptin started to decrease at 24 h of fasting in the SCI group, whereas plasma leptin started to decrease at 12 h of fasting in the AB group. The current study demonstrated that plasma leptin decreased with fasting in both SCI and AB groups, with the leptin decrease being delayed in the SCI group. The delayed leptin response to fasting in the SCI group may be because of increased fat mass (%body fat, SCI: 33.8 +/- 3.0, AB: 24.1 +/- 2.9) and sympathetic nervous system dysfunction.     

Adaptation of intestinal production of apolipoprotein A-IV during chronic feeding of lipid

We examined the effect of daily fat supplementation on intestinal gene expression and protein synthesis and plasma levels of apolipoprotein A-IV (apo A-IV). Rats were fasted overnight and then given intragastric bolus infusion of either saline or fat emulsion after 0, 1, 2, 4, 8, or 16 days of similar daily feedings. Four hours after the final saline or fat infusion, plasma and jejunal mucosa were harvested; plasma levels of apo A-IV, triglycerides, and leptin were measured, as well as mucosal apo A-IV mRNA levels and biosynthesis of apo A-IV protein. In response to fat, plasma apo A-IV showed an initial 40% increase compared with saline-injected control rats; with continued daily fat feeding, the plasma A-IV response showed rapid and progressive diminution such that by 4 days, plasma A-IV was not different between fat- and saline-fed groups. Jejunal mucosal apo A-IV synthesis and mRNA levels also showed time-dependent refractoriness to fat feeding. However, the kinetics of this effect were considerably slower than in the case of plasma, requiring 16 days for completion. There was no correlation between plasma leptin or triglyceride levels and intestinal apo A-IV synthesis or plasma apo A-IV. These results indicate rapid, fat-induced, posttranslational adapation of plasma apo A-IV levels and a slower, but similarly complete pretranslational adaptation of intestinal apo A-IV production, which are independent of plasma levels of leptin.