Short-term treatment with olanzapine reduces fasting plasma free fatty acid concentrations and hampers insulin action on glucose disposal in healthy men, whereas haloperidol has less clear effects. Moreover, olanzapine, but not haloperidol, blunts the insulin-induced decline of plasma free fatty acids and triglyceride concentrations. Notably, these effects come about without a measurable change of body fat mass.
We studied the impact of central GLP-1 receptor (GLP-1R) antagonism on the metabolic effects of peripheral GLP-1 administration in mice. High-fatfed insulin-resistant C57Bl/6 mice were treated with continuous subcutaneous infusion of GLP-1 or saline (PBS) for 2 wk, whereas the GLP-1R antagonist exendin-9 (EX-9) and cerebrospinal fluid (CSF) were simultaneously infused in the left lateral cerebral ventricle (icv). Glucose and glycerol turnover were determined during a hyperinsulinemic euglycemic clamp. VLDL-triglyceride (VLDL-TG) production was determined in hyperinsulinemic conditions. Our data show that the rate of glucose infusion necessary to maintain euglycemia was significantly increased by GLP-1. Simultaneous icv infusion of EX-9 diminished this effect by 62%. The capacities of insulin to stimulate glucose disposal and inhibit glucose production were reinforced by GLP-1. Simultaneous icv infusion of EX-9 significantly diminished the latter effect. Central GLP-1R antagonism alone did not affect glucose metabolism. Also, GLP-1 treatment reinforced the inhibitory action of insulin on VLDL-TG production. In conclusion, peripheral administration of GLP-1 reinforces the ability of insulin to suppress endogenous glucose and VLDL-TG production (but not lipolysis) and boosts its capacity to stimulate glucose disposal in high-fat-fed C57Bl/6 mice. Activation of central GLP-1Rs contributes substantially to the inhibition of endogenous glucose production by GLP-1 treatment in this animal model. glucagon-like peptide-1; gut hormone; exendin-9; central receptor; hyperinsulinemic euglycemic clamp; insulin-resistant animal model GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is produced by enteroendocrine L cells in response to food intake (21, 22). Circulating GLP-1 plays a major role in the control of postprandial metabolism, since it augments nutrient-induced insulin release (13, 21), inhibits glucagon secretion (36), and reduces endogenous glucose production (EGP) through (peripheral?) mechanistic routes that appear to be independent of islet hormones (32). Circulating GLP-1 also inhibits food intake probably via vagal afferents activating neurons in the nucleus of the solitary tract that subsequently project to hypothalamic neurons to blunt appetite (6, 40). Thus, circulating GLP-1 has multiple effects on postprandial behavior and metabolism to coordinate the systemic response to food intake.GLP-1 is also produced in a discrete population of neurons in the hindbrain (11,15), and GLP-1 fibers terminate in the arcuate and paraventricular nucleus of the hypothalamus (15), brain areas that play key roles in the control of metabolism (35). GLP-1 receptors are expressed abundantly in these nuclei (9, 27), and recent evidence indicates that activation of arcuate GLP-1 receptors sensitizes the liver to insulin, at least as far as its impact on glucose production is concerned (34). Despite compelling evidence that GLP-1 can cross the blood-brain barrier (17)
MATERIALS AND METHODS
Animals and diet.Male C57Bl/6J mice (12 wk old; Charles Rive...
High fat feeding induces a variety of obese and lean phenotypes in inbred rodents. Compared to Diet Resistant (DR) rodents, Diet Induced Obese (DIO) rodents are insulin resistant and have a reduced dopamine receptor D2 (DRD2) mediated tone. We hypothesized that this differing dopaminergic tone contributes to the distinct metabolic profiles of these animals.
C57Bl6 mice were classified as DIO or DR based on their weight gain during 10 weeks of high fat feeding. Subsequently DIO mice were treated with the DRD2 agonist bromocriptine and DR mice with the DRD2 antagonist haloperidol for 2 weeks.
Compared to DR mice, the bodyweight of DIO mice was higher and their insulin sensitivity decreased. Haloperidol treatment reduced the voluntary activity and energy expenditure of DR mice and induced insulin resistance in these mice. Conversely, bromocriptine treatment tended to reduce bodyweight and voluntary activity, and reinforce insulin action in DIO mice.
These results show that DRD2 activation partly redirects high fat diet induced metabolic anomalies in obesity-prone mice. Conversely, blocking DRD2 induces an adverse metabolic profile in mice that are inherently resistant to the deleterious effects of high fat food. This suggests that dopaminergic neurotransmission is involved in the control of metabolic phenotype.
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