Browsing by Subject "Starvation"
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Item Anorexia nervosa(1980-05-22) Gomez-Sanchez, Celso E.Item Essential Function of Ghrelin in Chronic Starvation(2013-02-22) Li, Robert Lin; Elmquist, Joel; Brown, Michael S.; Goldstein, Joseph L.; Cobb, Melanie H.; Kliewer, Steven A.Ghrelin, an octanoylated peptide hormone secreted from the stomach, stimulates the release of growth hormone (GH) from the pituitary. Ghrelin O-acyltransferase (GOAT) is the enzyme required for the attachment of octanoate to serine-3 of ghrelin, a step essential for making active ghrelin. In this study, we eliminated the Goat gene from mice to produce Goat –/– mice that lack octanoylated ghrelin. These mice were indistinguishable in weight from their wild-type (WT) littermates in when fed either a normal or a high fat diet. On 60% calorie restriction, WT and Goat –/– mice lost 30% of their body weight and 75% of their body fat within the first 4 days. While fasting blood glucose levels declined at the same rate initially in WT and Goat –/– mice, levels in the WT mice stabilized at 58–76 mg/dL after 4 days of 60% calorie restriction. In contrast, fasting blood glucose levels in the calorie restricted Goat –/– mice continued declining to 12–36 mg/dL by day 7, at which point the mice were moribund. Levels of ghrelin and GH rose progressively in WT mice during the calorie restriction. GH levels in Goat –/– mice, which have no ghrelin, rose to a much lesser degree, a phenotype also seen in calorie restricted Preproghrelin –/– mice that lack both ghrelin and des-acyl ghrelin. Restoring ghrelin or GH via an osmotic minipump to calorie restricted Goat –/– mice rescued their hypoglycemia. Thus, ghrelin is essential for survival during severe calorie restriction by elevating GH levels to preserve blood glucose and maintain life. The decreased elevation of GH in calorie restricted Goat –/– mice was associated with decreased plasma levels of two gluconeogenic substrates: pyruvate and lactate. Injections of exogenous pyruvate, lactate, and alanine to calorie restricted Goat –/– mice prevented the development of hypoglycemia. Injections of exogenous octanoate to calorie restricted Goat –/– mice, which spares the need to oxidize glucose and gluconeogenic substrate in the tricarboxylic (TCA) cycle to provide energy for gluconeogenesis, also prevented the hypoglycemia. Therefore, the preservation of blood glucose during calorie restriction by the ghrelin-mediated rise in GH involves the maintenance of adequate plasma levels of gluconeogenic substrates. The dramatic rise in plasma ghrelin during chronic severe calorie deprivation is essential to maintain life. However, the mechanism for this increase is not understood. From tissue culture cells derived from mice bearing ghrelinomas induced by a tissue-specific SV40 T-antigen transgene, we found that ghrelin secreting cells express high levels of mRNA encoding the β1-adrenergic receptor. Ghrelin secretion from these cells was stimulated by the addition of norepinephrine or epinephrine, an effect blocked by atenolol, a selective β1-adrenergic antagonist. Treating WT mice with atenolol or reserpine, a drug that depletes adrenergic neurotransmitters from sympathetic neurons, blocked the fasting-induced increase in plasma ghrelin. Thus, ghrelin secretion during fasting is induced by adrenergic agents released by sympathetic neurons which act directly on β1 receptors on the ghrelin-secreting cells of the stomach.Item Starvation Response in Caenorhabditis elegans(2009-01-14) Kang, Chanhee; Avery, LeonWhen the supply of environmental nutrients is limited, multicellular animas can make physiological and behavioral changes so as to cope with nutrient starvation. Although starvation response is essential for the survival of animals during nutrient deprivation, uncontrolled or uncoordinated starvation responses could be harmful. Autophagy, a lysosomal degradation pathway for long-lived proteins and cytoplasmic organelles, is known to be an important starvation response, which promotes both cell and organism survival by providing fundamental building blocks to maintain energy homeostasis during starvation. Under different conditions, however, autophagy may instead act to promote cell death through an autophagic cell death pathway. Why autophagy acts in some instances to promote survival but in others to promote death is poorly understood. Here I show that physiological levels of autophagy act to promote survival in Caenorhabditis elegans during starvation, whereas insufficient or excessive levels of autophagy contribute to death. I find that inhibition of autophagy decreases survival of wildtype worms during starvation. Furthermore, I find that in gpb-2 starvationhypersensitive mutants, starvation induces excessive autophagy in pharyngeal muscles, which in turn, causes damage that may contribute to death. These results demonstrate that, depending on level of its activation, autophagy can have either prosurvival or prodeath functions, providing in vivo evidence that an uncontrolled starvation response could be harmful to animals. Thus, it is important that animals ensure that their starvation response is coordinated between individual cells. However, the mechanisms by which animals sense starvation systemically remain elusive. Here I use gpb-2 mutants to identify molecules and mechanisms that modulate starvation signaling. I found that specific amino acids could suppress the starvation-induced death of gpb-2 mutants, and that MGL-1 and MGL-2, C. elegans homologs of metabotropic glutamate receptors, were involved. MGL-1 and MGL-2 acted in AIY and AIB neurons respectively. Treatment with leucine suppressed starvation-induced stress resistance and life span extension in wild-type worms, and mutation of mgl-1 and mgl-2 abolished these effects of leucine. Theses results suggest that metabotropic glutamate receptor homologs in AIY and AIB neuron may modulate a systemic starvation response in C. elegans.Item Starvation-Signaling in the Nematode Caenorhabditis Elegans Using Regulator of G-Proteins GPB-2(2013-08-30) Pollok, Robert Harding; Galindo, Rene; Avery, Leon; Abrams, John M.; Castrillon, Diego H.During starvation, C. elegans adjust their behavior in order to survive. Using the starvation-sensitive gpb-2(ad541) loss-of-function mutant, components in a starvation-signaling pathway were identified. The goals of the studies presented here were to identify neurons that propagate a starvation signal, and to identify genes that regulate fat storage in the gut during starvation. Starvation in gpb-2(ad541) worms is lethal, and this lethality can be induced by arecoline, an acetylcholine receptor antagonist. Starvation sensitivity in gpb-2(ad541) worms is inhibited by atropine, an acetylcholine receptor antagonist. Previous work suggests that cholinergic signaling propagates a starvation signal in the pharynx of the worm, and the MC neurons are responsible for sending that signal. By ablating the MC neurons in newly hatched L1 worms, I aimed to prevent starvation-induced lethality due to the gpb-2(ad541) background. Several genes have also been identified to act downstream of gpb-2 in the regulation of fat in the gut. Both flp-20 loss-of-function and mgl-2 loss-of-function mutations rescue the starvation-induced lethality of gpb-2(ad541), while introduction of a gcy-28 loss-of-function mutation restores lethality. When fat was assayed using Oil Red O, it was found that GCY-28, a receptor-type guanylate cyclase, is necessary to maintain fat levels during starvation. GCY-28 is expressed in various head neurons and throughout the gut, and GCY-28 may play a role in regulating how gut cells store fat.Item [UT Southwestern Medical Center News](2008-06-27) McKenzie, AlineItem [UT Southwestern Medical Center News](2010-12-26) Shear, Kristen Holland