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Intestinal gluconeogenesis is involved in the control of food intake. We show that mu-opioid receptors (MORs) present in nerves in the portal vein walls respond to peptides to regulate a gut-brain neural circuit that controls intestinal gluconeogenesis and satiety. In vitro, peptides and protein digests behave as MOR antagonists in competition experiments. In vivo, they stimulate MOR-dependent induction of intestinal gluconeogenesis via activation of brain areas receiving inputs from gastrointestinal ascending nerves. MOR-knockout mice do not carry out intestinal gluconeogenesis in response to peptides and are insensitive to the satiety effect induced by protein-enriched diets. Portal infusions of MOR modulators have no effect on food intake in mice deficient for intestinal gluconeogenesis. Thus, the regulation of portal MORs by peptides triggering signals to and from the brain to induce intestinal gluconeogenesis are links in the satiety phenomenon associated with alimentary protein assimilation.

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Unlike SPL, MPL in the high-fat diet did not induce WAT hypertrophy and inflammation but increased colonic goblet cells. This supports further clinical exploration of different sources of dietary emulsifiers in the frame of obesity outbreak.

ObjectivesCertain nutrients positively regulate energy homeostasis via intestinal gluconeogenesis (IGN). The objective of this study was to evaluate the impact of a deficient IGN in glucose control independently of nutritional environment.MethodsWe used mice deficient in the intestine glucose-6 phosphatase catalytic unit, the key enzyme of IGN (I-G6pc−/− mice). We evaluated a number of parameters involved in energy homeostasis, including insulin sensitivity (hyperinsulinemic euglycaemic clamp), the pancreatic function (insulin secretion in vivo and in isolated islets) and the hypothalamic homeostatic function (leptin sensitivity).ResultsIntestinal-G6pc−/− mice exhibit slight fasting hyperglycaemia and hyperinsulinemia, glucose intolerance, insulin resistance and a deteriorated pancreatic function, despite normal diet with no change in body weight. These defects evoking type 2 diabetes (T2D) derive from the basal activation of the sympathetic nervous system (SNS). They are corrected by treatment with an inhibitor of α-2 adrenergic receptors. Deregulation in a key target of IGN, the homeostatic hypothalamic function (highlighted here through leptin resistance) is a mechanistic link. Hence the leptin resistance and metabolic disorders in I-G6pc−/− mice are corrected by rescuing IGN by portal glucose infusion. Finally, I-G6pc−/− mice develop the hyperglycaemia characteristic of T2D more rapidly under high fat/high sucrose diet.ConclusionsIntestinal gluconeogenesis is a mandatory function for the healthy neural control of glucose homeostasis.

Protein-enriched diets are well known to initiate satiety effects in animals and humans. It has been recently suggested that this might be dependent on the induction of gluconeogenesis in the intestine. The resulting intestinal glucose release, detected by a "so-called" glucose sensor located within the walls of the portal vein and connected to peripheral afferents, activates hypothalamic nuclei involved in the regulation of food intake, in turn initiating a decrease in hunger. To definitively demonstrate the role of intestinal gluconeogenesis in this mechanism, we tested the food intake response to a protein-enriched diet in mice with an intestine-specific deletion (using an inducible Cre/loxP strategy) of the glucose-6 phosphatase gene (I-G6pc(-/-) mice) encoding the mandatory enzyme for glucose production. There was no effect on food intake in I-G6pc(-/-) mice fed on a standard rodent diet compared to their wild-type counterparts. After switching to a protein-enriched diet, the food intake of wild-type mice decreased significantly (by about 20% of daily calorie intake), subsequently leading to a decrease of 12 ± 2% of initial body weight after 8 days. On the contrary, I-G6pc(-/-) mice were insensitive to the satiety effect induced by a protein-enriched diet and preserved their body weight. These results provide molecular evidence of the causal role of intestinal gluconeogenesis in the satiety phenomenon initiated by protein-enriched diets.

Bovine fasciculata adrenal cells contain specific high-affinity (KD 2.3 ± 0.4 X 10-10 M) and low-capacity (1910 ± Corticotropin (ACTH) is the main hormone in mammals that regulates glucocorticoid secretion. However, detection and characterization of physiologically relevant ACTH receptors have been difficult (for review, see ref. 1), because of the low biological activity of the labeled ACTH, which was probably related to the introduction of a bulky iodine atom into Tyr-2 (2) and to the oxidation of Met-4 (3). These difficulties were overcome by synthesizing an analog of ACTH in which Tyr-2 was replaced by Phe and Met-4 was replaced by norleucine (4,5) or by using '25I-labeled ACTH labeled only on Tyr-23 (6). Using these labeled hormones, physiologically relevant ACTH receptors have been characterized in rat (5, 7), human (8), and domestic fowl (6) adrenal cells. However, the regulation of adrenal-cell ACTH receptors has only been investigated once in vivo (9) and twice in vitro (10, 11) and the results are contradictory. The first study (9) indicated that ACTH has a positive effect on its own receptors, whereas the results of the in vitro studies suggest the absence of such an effect (10,11 Cell Culture and Binding Studies. Bovine adrenocortical fasciculata cells were prepared and cultured in a serum-free medium (12, 13). On the second day of culture the medium was removed and replaced with fresh medium alone or with the factors indicated. At the end of this experimental period, the medium was removed, and the cells were washed twice with ice-cold 0.9% NaCl, once with ice-cold acidic glycine buffer (50 mM glycine/100 mM NaCl, pH 3) for 4.5 min at 4°C, and twice with 0.9% NaCl, to remove the membranebound ligands (12). Then the cells were incubated for 1 hr at 20°C with 0.1 pmol of 125I-ACTH in F-12/DMEM containing 0.5% bovine serum albumin and 0.1% bacitracin. At the end of the incubation, the medium was removed and the cells were washed three times with 0.9% NaCl and then dissolved in 0.5 M NaOH/0.4% sodium deoxycholate. The radioactivity was measured in a y counter with 75% efficiency. All the binding assays were performed in triplicate. Specific binding was determined by subtracting from the total binding the radioactivity associated with cells in the presence of 10-6 nonradioactive ACTH. This nonspecific binding accounted for at most 10% of the total binding. On molar basis, ACTH-(1-39) and ACTH-(1-24) were equipotent to displace bound 125I-ACTH and to stimulate cAMP and steroid production.Other Methods. To test the functional activity of the adrenal cells, at the end of each experimental protocol, the cells were washed as described above and incubated in fresh medium alone or with effectors. One aliquot of the medium was taken after 1 hr for cAMP determination and another was taken after 2 hr for steroids; both were frozen until assay by a specific radioimmunoassay (12). Statistical analysis was performed with Student's t test for comparison oftwo groups. Differences were considered significant w...

In several species, including the human fetus, insulin-like growth factors (IGF-I and IGF-II) have been reported to modulate adrenal steroidogenesis, thus contributing to adrenal cortical differentiation. In the present study, we examined the long term effects of IGF-I and -II on human adult adrenal fasciculata-reticularis cells cultured in a chemically defined medium and compared them to the effects of insulin, human GH, and ACTH. Treatment for 3 days with IGF-I or -II at nanomolar concentrations or with insulin at micromolar concentrations slightly increased the production of androstenedione, cortisol, and dehydroepiandrosterone about 1.5-fold over that by control cells. Moreover, the acute steroidogenic response to ACTH of cells pretreated with IGF-I, IGF-II, or insulin was 3- to 6-fold higher than that of control cells. For each hormone, these effects of IGF-I and -II were dose dependent between 0.1-26 nmol/L (1-200 ng/mL). The secretion of androstenedione was more potently stimulated than that of dehydroepiandrosterone and cortisol, and this effect was more clearly yielded by pretreatment with IGF-II than with IGF-I or insulin. Human GH had no effect on these cells. In cells treated with IGF-I or -II, the messenger ribonucleic acid (mRNA) levels of cytochrome P450 17 alpha-hydroxylase and of 3 beta-hydroxysteroid dehydrogenase were increased, and the abundance of ACTH receptor mRNA was also slightly enhanced, but the mRNA of cytochrome P450 cholesterol side-chain cleavage enzyme was unchanged. In conclusion, IGFs enhance the steroidogenesis and ACTH responsiveness of human adrenocortical cells in culture. We speculate, that by this mechanism, IGFs may contribute to clinical states with hyperandrogenemia.