Similarities and differences in the transcriptional regulation of the leptin gene promoter in gastric and adipose cells.

The stomach was reported to synthesize and secrete leptin mainly in the gastric lumen. Gastric leptin release is markedly increased after food intake, by vagal cholinergic stimulation and by cholecystokinin and secretin. Here we show that human gastric MKN-74 cells produce leptin that increases upon challenge with cholecystokinin, insulin, glucocorticoids and all-trans retinoic acid through activation of the leptin gene promoter. In addition, we demonstrate that forskolin and BRL37344 which increased cAMP levels, fail to affect the activity of leptin gene promoter in MKN74 expressing beta(3)-adrenoceptor cells but, induce a 2-fold decrease in this activity in adipose 3T3-L1 cells. These data described for the first time, similarities and more interestingly, differences in the regulation of the leptin gene promoter in gastric cells as compared to adipocytes.

Effects of zidovudine, stavudine and beta-aminoisobutyric acid on lipid homeostasis in mice: possible role in human fat wasting.

OBJECTIVE: Although mitochondrial DNA (mtDNA) depletion could play a role in nucleoside reverse transcriptase inhibitor-induced lipoatrophy, poor correlations between fat mtDNA levels and lipoatrophy suggest additional mechanism(s). Stavudine (d4T), zidovudine (AZT) and the thymine catabolite, beta-aminoisobutyric acid (BAIBA), but not zalcitabine (ddC) or didanosine (ddI), can increase fatty acid oxidation in liver mitochondria and plasma ketone bodies in mice. Since fat oxidation in non-adipose tissue can influence body adiposity, we sought to determine whether d4T, AZT and BAIBA can cause lipoatrophy in mice by this catabolic mechanism. METHODS: Lean or obese ob/ob mice were treated for 6 weeks with d4T, AZT or BAIBA, and lean mice with ddC or ddI. Body fat mass was assessed by dual energy X-ray absorptiometry, and mtDNA by Slot blot hybridization in epididymal fat. RESULTS: Whereas ddC or ddI did not change plasma beta-hydroxybutyrate and body fat mass, d4T, AZT and BAIBA increased plasma beta-hydroxybutyrate in lean mice suggesting increased hepatic fatty acid oxidation and ketogenesis. Despite unchanged food consumption, a supra-pharmacological dose of d4T tended to decrease, whilst AZT and BAIBA decreased body fat mass. Fat mtDNA and plasma triglycerides, cholesterol, glucose, insulin, leptin and adiponectin levels were unchanged. In obese mice, d4T, AZT and BAIBA did not increase plasma beta-hydroxybutyrate, and only AZT decreased body fat mass without reducing fat mtDNA. CONCLUSIONS: d4T and AZT can enhance hepatic fat oxidation and cause fat wasting, without decreasing adipose tissue mtDNA and without causing insulin resistance in mice. BAIBA, a thymine catabolite, reproduces these effects. These catabolic effects could play a role in the lipoatrophy, which can occur in AZT- or d4T-treated patients.

Leptin reduces the development of the initial precancerous lesions induced by azoxymethane in the rat colonic mucosa.

BACKGROUND & AIMS: Recent studies suggest that leptin, a hormone involved in food intake regulation, released into the circulation and gastrointestinal juice, may be a growth factor for intestine and may be involved in carcinogenesis; however, data are contradictory. This study investigates in rat colonic mucosa (1) the effects of hyperleptinemia on epithelial cell proliferation and development of aberrant crypts, earliest preneoplastic lesions, and (2) whether luminal leptin affects cell proliferation. METHODS: Leptin (1 mg/kg/d) or vehicle was administered systemically by miniosmotic pump in Fischer 344 rats either for 7 days (BrdU-labeling indices study) or 23 days (azoxymethane-induced colonic lesions study). The effects of injections or continuous infusion of leptin into the colon were also studied. RESULTS: In systemic leptin-treated rats, plasma leptin levels were 4- to 5-fold increased (P < 0.008 to P < 0.001); labeling indices were higher in proximal colon than in pair-fed control rats (P = 0.006) but unaffected in distal colon. Unexpectedly, in azoxymethane-treated rats, leptin significantly inhibited aberrant crypt foci formation in the middle and distal colon compared with controls (P = 0.006). Under these conditions, plasma insulin levels were reduced by 41%-58%, but gastrin levels were unchanged. In controls, luminal immunoreactive leptin reached the colon. A 3.6-fold increase in intraluminal leptin had no effect on epithelial cell proliferation. CONCLUSIONS: This study provides the first evidence that leptin reduces the development of chemically induced precancerous lesions in colon, perhaps through decreased insulinemia, and thus does not support an important role for leptin in carcinogenesis promotion. Moreover, the study indicates that leptin is not a potent growth factor for normal intestine.

Duodenal leptin stimulates cholecystokinin secretion: evidence of a positive leptin-cholecystokinin feedback loop.

Some of the actions of leptin depend on cholecystokinin (CCK). However, it is unknown whether leptin modulates the release of CCK. Here, we demonstrate in vitro that leptin induces the phosphorylation of extracellular signal-related kinase (ERK)-1/2 proteins and increases CCK release (EC(50) = 0.23 nmol/l) in CCK-secreting STC-1 cells. We showed that rat duodenal juice contains leptin that circulates free and bound to macromolecules, suggesting that leptin has a lumenal action on the intestine. In vivo in the rat, duodenal infusion of leptin increased plasma CCK at levels comparable to those induced by feeding. Moreover, meal-induced increases in plasma CCK were markedly reduced in obese fa/fa rats, whereas the mobilization of the gastric leptin pool was similar in lean and obese Zucker rats. The release of CCK by leptin presumably generates a positive feedback loop. Indeed, the blockade of CCK receptors reversed the meal reduction of the stomach leptin pool and the meal-increased plasma insulin, consistent with the previous concept of an entero-insular axis. Collectively, these data support a novel mode of action of leptin where leptin and CCK may potentiate their own effects by cross-stimulating their secretion. The impairment of this leptin-CCK loop may have pathological implications related to obesity and diabetes.

Vagal stimulation rapidly increases leptin secretion in human stomach.

BACKGROUND & AIMS: Leptin production has been reported in the rat and in human stomach. It initiates intestinal nutrient absorption. In this study, we analyzed the effect of vagal stimulation on leptin release in the human stomach. METHODS: We studied the secretion of gastric acid and leptin on stimulation with insulin (a stimulant of vagal pathways via hypoglycemia) and pentagastrin in 11 healthy men (normal endoscopy and normal histological gastric mucosa), 5 with previous highly selective vagotomy (HSV), and 6 without HSV. Fundic biopsies were performed for immunostaining of leptin. RESULTS: There was no difference between the 2 groups with respect to age, body mass index, basal leptin (4.8 +/- 1.2 ng/15 minutes) and gastric acid (0.7 +/- 0.2 mmol/15 minutes) outputs. Leptin-immunoreactivity was found in the fundic glands, and its distribution and density were similar in 2 groups. Insulin caused a rapid (15-minute) increase in leptin output in men without HSV (31 +/- 9 ng/15 minutes), but not in those with HSV (7.7 +/- 3.2 ng/15 minutes). Insulin-stimulated gastric leptin was biphasic, with a rapid increase (15 minutes after injection) followed by a second steady and sustained increase (39.9 +/- 7.6 ng/15 minutes at 120 minutes after injection). Pentagastrin increased gastric leptin output in individuals with (30 +/- 4.9 ng/15 minutes) and without (26 +/- 3.2 ng/15 minutes) HSV. Insulin and pentagastrin did not modify plasma leptin, whatever HSV status. CONCLUSIONS: Vagal stimulation of leptin release in the human stomach suggests that leptin is released during the cephalic phase of gastric secretion. Luminal leptin may be involved in vagus-mediated intestinal functions.