current topics (obesity and hormones) exam 2 finaallll

AgRP levels have been shown to change with pregnancy and lactation. Explain these changes and why this would be important.

AgRP levels have been shown to be elevated throughout pregnancy and lactation. These changes are significantly important due to the fact that AgRP induces feeding behavior. Throughout pregnancy, there is an increased demand on energy consumption for both the parent and fetus. In other words, parents will eat more food to feed their young.

Is cholecystokinin (CCK) anorexigenic or orexigenic? Where is it secreted from? What are its targets?

-Cholecystokinin is an anorexigenic hormone released from the gastrointestinal tract (cells of the upper small intestine) -plays a role in facilitating digestion -secretion triggered by introduction of HCl, amino acids, or fatty acids into the stomach or duodenum -stimulates gallbladder contraction and release stored bile into the intestine -thought to induce satiety -stim. release of pancreatic juice -thought to induce satiety -CCK is mainly secreted from the pancreas as well to act upon the gall bladder. -CCK has a wide range of targets, including gall bladder contraction and secretion, pancreatic secretion, decreased gastric acid secretion, and decreased gastric emptying. Therefore, the physiological roles of CCK are primarily responsible for the actions of the gastrointestinal tract. -The regions to which CCK is secreted from depend on the locations of the CCK receptors. -CCK-A and CCK-B are the two CCK receptors, whereas CCK-A is specified as the "alimentary type" and CCK-B is the "brain type".

melanin-concentrating hormone (MCH) (effects on body weight and secretions) (fasting in mice, injections into mice effects and where)

-Fasting increased expression of MCH in both normal and obese mice -Neurons containing MCH are located in the zona incerta and in the lateral hypothalamus (areas are involved in regulation of ingestive behavior) but role of MCH is unknown -Injected MCH into lateral ventricles of rats → food consumption increased -Fasting led to an MCH increase in all mice tested -Cyclic, 19-amino-acid neuropeptide -Neuropeptide -Agouti protein may cause obesity by mimicking action of orexigenic peptide MCH in the hypothalamus -Orexigenic -No studies have shown effects on energy expenditure and secretion of insulin (or other metabolic hormones) -These findings suggest that MCH participates in the hypothalamic regulation of body weight

In the Asnicar paper, CART deficient mice were created. CART +/+ (wild type), CART +/- (partial deletion of CART), and CART -/- (complete deletion of CART) had different phenotypes depending on sex (male or female) and the diet they were fed. Explain these differences. How might estradiol or testosterone influence these differences? (long af)

-Feeding study on high fat chow diet: 29 week period -Feeding study on regular chow: 14 weeks -High fat diet: ~Male CART -/- mice: increase in weekly food consumption, increase in fat masses greater than WT beginning at 8th week of study) in comparison with wild type controls ~Male CART +/- mice: not different from their wild type littermates ~Female CART -/- mice: significantly higher fat masses than their wild type littermates (increased significantly after 15th week of feeding study); increased food intake ~Female CART +/- mice: significantly higher fat masses than their wild type littermates (increased significantly after 15th week of feeding study); increased food intake ~Body weight differences in female CART -/- and CART +/- mice became statistically significant only after 10th and 13th week, respectively -Regular chow diet: ~Fed regular diet for 14 weeks at 17 weeks of age ~No body weight differences were shown among WT, CART -/-, and CART +/- mice of the same gender ~Significant mean body weight increase in CART -/- or female CART +/- mice fed a high fat diet compared with the mice of the same genotypes fed regular chow diet at this age -Absence of CART expression induces adiposity when the mice were fed a calorically-rich diet -Male CART +/- mice had a phenotype similar to that of male wild type mice, whereas female CART +/- mice behaved like female CART -/- mice → phenotypic differences between male and female CART +/- mice may be attributable to gender-base differential CART expression in specific areas of the brain (apply to estradiol and testosterone → females contain higher concentrations of estradiol, and both female CART mutant mice increased food consumption when fed high fat diets, thus suggesting that estradiol increases the demand of adiposity in means that females require more adipose concentrations than males; only the male mice that were completely deficient in CART expressed increased high fat diet consumption, therefore testosterone may control the need of adipose concentrations in males when they were partly deficient)

Is Agouti-related Protein (AgRP) anorexigenic or orexigenic? Where is it secreted from and what other hormone is co-secreted/co-localized in the hypothalamus with it? What are its targets?

-Orexigenic peptide co-secreted with NPY -Subpopulation of hypothalamic neurons coexpress AgRP and NPY in the arcuate nucleus of the hypothalamus -Profound stimulation of food intake (stimulation of hyperphagia) -Targets various peripheral hormonal signals such as leptin, ghrelin, and insulin -Acts to suppress energy expenditure -Regulates hypothalamic pituitary axis (shown by injection of human AgRP in rhesus monkeys) -Found in both orthologs of the hypothalamus, the subthalamic nucleus, and at lower expression levels in the testis, lung, kidney, spinal cord, and dorsal root ganglia -Counteract proopiomelanocortin (POMC-expressing neurons) which are anorexigenic in the arcuate nucleus -Antagonist of the action of alpha-melanocyte stimulating hormone at the melanocortin receptors (MCR) -AgRP expressed in the periphery (AgRP in the adrenal gland) -Play a significant role in the hypothalamic regulation of enery homeostasis -Ablation of AgRP has been shown to produce acute anorexia, therefore AgRP may play a role in increased feeding behavior

Orexin has been implicated in contributing to the rewarding effects of food. Explain the brain areas/circuitry underlying orexin's effects on food reward.

-Sweet substances specifically linked -Stimulates appetite (orexigenic) -Mesolimbic dopamine circuit (surrounds hypothalamus) -LH: involved in motivated behavior for drugs of abuse as well as natural rewards (lateral hypothalamus) (and preference for food) -VTA: implicated in intake of high-fat food (projection of NAc to hypothalamic orexin neurons in turn project to VTA) -NAc: regulation of reward-related behaviors (nucleus accumbens) -PeF/DMH: innervated by other hypothalamic regions involved in homeostatic and arousal-related drive states -Ghrelin stimulates GH release from pituitary cells (pituitary gland) -Arcuate nucleus: NPY neurons in arcuate nucleus regulate food intake -Amygdala

There are transgenic mice that overexpress AgRP. What is their phenotype? How do they differ from normal mice?

-Transgenic mice over-expressing AgRP exhibit severe obesity, have increased body length, hyperinsulinemia, late-onset hyperglycemia, pancreatic islet hyperplasia, and reduced corticosterone levels -In the fed state, expression of AgRP is double in obese mice than in normal mice -Overexpressed AgRP also promotes yellow hair color because agouti is normally expressed within the hair follicle

CCK has many physiological functions other than appetite regulation. Give at least 2 examples and explain.

As mentioned in one of the articles, fat has an inhibitory effect on gastric emptying. CCK inhibits gastric emptying. This specific role of CCK was tested by administration of loxiglumide, a CCK receptor antagonist, which was shown to perform the opposite effect on gastric emptying. CCK stimulates gall badder contraction as well. Ivy and Goldberg have conducted an experiment involving the administration of lipid into the small intestine, which stimulated contraction of the gall bladder. Therefore, CCK was officially discovered as the stimulator for this action. CCK's physiological role on the action of the gall bladder has been concluded when devazepide, a CCK receptor antagonist, was shown to inhibit gall bladder contraction. -slowing down gastric emptying when delivered through exogenous administration -when gastric emptying slowed down, it is associated with proximal gastric relaxation, suppression of antral and duodenal pressure waves and stimulation of tonic and phasic pyloric pressures, stimulation of jejunum, and suppression of colonic activity

CCK mutations have been implicated to contribute to development of obesity. Take either a pro or con stance on this and explain either why or why not CCK contributes to the pathogenicity of obesity.

I feel that CCK mutations do not contribute to the development of obesity primarily because throughout a period of time when both obese and healthy subjects were administered acute intravenous infusion of exogenous CCK, both were shown to have the same satiating outcome. Fasting CCK plasma concentrations of obese individuals were reported to be increased rather than decreased as well, indicating senses of satiety after food consumption. Mutations of the CCK1 gene in humans are fairly rare as well.

What are the effects of intercerebroventricular (ICV) injections of AgRP? When were they injected?

Intercerebroventricular injections of AgRP stimulates food intake. When AgRP was administered at the beginning of the feeding cycle, caloric consumptions have been shown to double.

AgRP has peripheral effects. How does it interact with cortisol, leptin, ghrelin, and glucose?

Leptin and insulin act to decrease AgRP concentration. When insulin acts to decrease AgRP, glucose concentrations will rise soon after. However, ghrelin acts to activate AgRP and NPY expression in order to stimulate feeding and body weight gain behaviors. Cortisol (glucocorticoids) have been shown to increase AgRP and NPY expressions.

It was suspected that rats given CCK in the Gibbs paper may have reduced food consumption because they were sick. How did the researchers test for this?

Temperature measurements were reported throughout the study, where both saline-injected and CCK-injected rats displayed normal temperature-measurement results. Taste aversion tests were used as well in order to induce the rats with ill associations toward the saccharin (used in the prior experiment) by administration of lithium chloride. The results have shown that none of the treatments following the experiment involving the use of saccharine have produced ill-related symptoms such as diarrhea nor abnormal amounts of water drunk.

What effects, if any, are observed after chronic (long-term) treatment with CCK? Why do you think this is?

The effects observed with chronic intravenous CCK-8 on rats did not involve any decreased food intake or body weight. Unlike acute administration of CCK-8, I feel that chronic administration reduces the body's sensitivities toward CCK-8 effects due to a sort of resistance development. In other words, long-term CCK-8 treatment may result in a tolerance of the receptors toward a significantly large amount of CCK demand. Therefore, the body's response will be abnormal and will not act upon the administration.