AGRP
Agouti-related protein precursor [AGRT] [ART]
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Psychological stress due to social isolation is known to cause abnormal feeding behaviors, but the influences of gender and aging on subchronic stress-induced changes in feeding behaviors are unknown. Thus, we examined the changes in body weight, food intake, and orexigenic ghrelin-related factors during 2 weeks of isolation stress in young and aged mice. Food intake increased significantly in young mice in the isolation group compared with the group-housed control throughout the experimental period. This isolation-induced increase in food intake was not observed in aged mice. In young mice, there were no significant differences in body weight between the isolated group and group-housed control up to 2 weeks. However, aged male mice exhibited significant weight loss at 2 weeks and a similar tendency was observed in aged female mice. Young male mice, but not female mice, had significantly increased (2.2-fold) plasma acylated ghrelin levels after 1 week of isolation compared with the group-housed control. A significant but lower increase (1.3-fold) was also observed in aged male mice. Hypothalamic preproghrelin gene expression decreased significantly with isolation in young male mice, whereas it increased significantly in female mice. The expression levels of NPY and AGRP in the hypothalamus, which are transmitted by elevated peripheral ghrelin signals, increased significantly in isolated young male mice, whereas the AGRP expression levels decreased significantly in young female mice. Isolation caused no significant differences in the expression levels of these genes in aged mice. In isolation, young female mice exhibited markedly increased dark- and light-phase locomotor activities compared with male mice, whereas male and female aged mice exhibited no obvious increases in activity immediately after the dark phase started. We conclude that the gender-specific homeostatic regulatory mechanisms required to maintain body weight operated during subchronic psychological stress in young mice but not in aged mice.
MeSH Terms
- Aging
- Animals
- Energy Intake
- Feeding Behavior
- Female
- Ghrelin
- Hypothalamus
- Male
- Mice, Inbred C57BL
- Motor Activity
- Sex Characteristics
- Social Isolation
- Stress, Psychological
Neuropeptide Y (NPY) stimulates feeding and weight gain, but deletion of the NPY gene does not affect food intake and body weight in mice bred on a mixed genetic background. We reasoned that the orexigenic action of NPY would be evident in C57Bl/6J mice susceptible to obesity. NPY deficiency has no significant effect in mice fed a normal rodent diet. However, energy expenditure is elevated during fasting, and hyperphagia and weight gain are blunted during refeeding. Expression of agouti-related peptide (AGRP) in the hypothalamus is increased in NPY knockout (NPYko) than wild-type mice, but unlike wild type there is no further increase in AGRP when NPYko mice are fasted. Moreover, NPYko mice have higher oxygen consumption and uncoupling protein-1 expression in brown adipose tissue during fasting. The failure of an increase in orexigenic peptides and higher thermogenesis may contribute to attenuation of weight gain when NPYko mice are refed. C57Bl/6J mice lacking NPY are also less susceptible to diet-induced obesity (DIO) as a result of reduced feeding and increased energy expenditure. The resistance to DIO in NPYko mice is associated with a reduction in nocturnal feeding and increased expression of anorexigenic hypothalamic peptides. Insulin, leptin, and triglyceride levels increase with adiposity in both wild-type and NPYko mice.
MeSH Terms
- Aging
- Animals
- Appetite
- Blood Glucose
- Body Weight
- Corticosterone
- Dietary Fats
- Eating
- Fasting
- Female
- Insulin
- Leptin
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Obese
- Neuropeptide Y
- Obesity
- Oxygen Consumption
- Thyroxine
- Weight Gain
In young (35- to 56-day-old) and middle-aged (9-mo-old) wild-type ( / ) and melanocortin-4 receptor (MC4R)-deficient ( /-, -/-) mice, expressions of neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin (POMC), and cocaine-and-amphetamine-regulated transcript (CART) were analyzed in the arcuate nucleus (ARC) and adjacent regions comprising the dorsomedial (DMN) and ventromedial (VMN) nucleus. In the ARC of young mice, NPY and AGRP expression increased and POMC and CART expression decreased with body fat content. Adjusting for the influence of body fat content by ANCOVA showed that the levels of NPY, POMC, and CART were highest and of AGRP lowest in young -/- mice. In the middle-aged mice, feedback from body fat content was weakened. For -/- mice ANCOVA revealed higher NPY and AGRP, lower POMC, and unchanged CART expression levels relative to young -/- mice. In the DMN and VMN, POMC and AGRP signals were absent at each age. CART was expressed in the DMN independent of age, fat content, and genotype. For NPY expression, an age-dependent induction was found in the DMN and VMN; it was absent in the young but present in the middle-aged mice, showing close positive correlations between body fat content and the numbers of NPY-labeled cells which were further enhanced in -/- mice. Thus MC4R deficiency augments age-induced NPY expression in the DMN and VMN with no feedback from body fat content. Negative feedback control by body fat content on ARC neuropeptide expression is present in young animals but vanishes with age and is modulated by MC4R deficiency.
MeSH Terms
- Adipose Tissue
- Aging
- Agouti-Related Protein
- Animals
- Arcuate Nucleus of Hypothalamus
- Gene Deletion
- Genotype
- Hypothalamus
- Intercellular Signaling Peptides and Proteins
- Leptin
- Mice
- Mice, Knockout
- Models, Animal
- Nerve Tissue Proteins
- Neuropeptide Y
- Neuropeptides
- Obesity
- Pro-Opiomelanocortin
- Proteins
- Receptor, Melanocortin, Type 4
Animal studies have demonstrated the importance of orexigenic NPY and agouti-related protein (AGRP) hypothalamic neurons, which are inhibited by the adipocyte hormone leptin, in the regulation of body weight and neuroendocrine secretion. We have examined NPY and AGRP neurons in postmortem human hypothalami from controls, Prader-Willi syndrome and other obese subjects, using quantitative immunocytochemistry (ICC) and in situ hybridization, to identify causes of leptin resistance in human obesity. Using combined ICC and in situ hybridization, AGRP, but not POMC, was colocalized with NPY in infundibular nucleus neurons. Infundibular nucleus (including median eminence) NPY ICC staining or mRNA expression, and AGRP ICC staining, increased with premorbid illness duration. NPY ICC staining and mRNA expression were reduced in obese subjects, but AGRP ICC staining was unchanged, correcting for illness duration. This suggests normal responses of NPY and AGRP neurons to peripheral signals, such as leptin and insulin, in human illness and obesity. The pathophysiology of obesity and illness-associated anorexia appear to lie in downstream or separate neuronal circuits, but the infundibular neurons may mediate neuroendocrine responses to illness. The implications for pharmacological treatment of human obesity are discussed.
MeSH Terms
- Adult
- Aged
- Aged, 80 and over
- Aging
- Agouti-Related Protein
- Cadaver
- Female
- Humans
- Hypothalamus
- Intercellular Signaling Peptides and Proteins
- Male
- Middle Aged
- Neuropeptide Y
- Obesity
- Postmortem Changes
- Prader-Willi Syndrome
- Preservation, Biological
- Proteins
- RNA, Messenger
- Sex Characteristics
- Tissue Distribution
- Tissue Fixation
During development there is novel expression of NPY mRNA in the dorsomedial hypothalamic nucleus (DMH) and perifornical region (PFR), in addition to the arcuate nucleus (ARH). Furthermore, NPY mRNA levels peak in all regions on postnatal d 16 (P16) and decrease to adult levels by P30. The purpose of the present study was to determine whether NPY and agouti-related protein (AGRP) mRNA expression in the different hypothalamic regions on P11 and P16 are similarly affected by fasting. An examination of the full rostral to caudal extent of the hypothalamus revealed two additional regions displaying novel NPY mRNA expression, the parvocellular division of the paraventricular nucleus (PVH) and lateral hypothalamus (LH). Maternal deprivation for 36 h, used to bring about a fast, similarly increased (23-29%) NPY and AGRP mRNA expression in the ARH on P11 and P16. In contrast, NPY expression in the DMH and PFR were significantly decreased (19-30% and 48-53%, respectively), whereas NPY mRNA levels in the PVH and LH were not altered by this treatment. The increase in NPY and AGRP mRNA expression in the ARH in response to maternal deprivation suggests that these neuronal populations respond to signals of energy balance. In contrast, NPY expression in the DMH, PFR, PVH, and LH is differentially regulated by maternal deprivation or other factors associated with maternal separation.
MeSH Terms
- Aging
- Agouti-Related Protein
- Animals
- Animals, Newborn
- Gene Expression
- Hypothalamic Area, Lateral
- Hypothalamus
- Intercellular Signaling Peptides and Proteins
- Maternal Deprivation
- Neuropeptide Y
- Paraventricular Hypothalamic Nucleus
- Proteins
- RNA, Messenger
- Rats
- Tissue Distribution