Behavioral, physiological, and molecular differences in response to dietary restriction in three inbred mouse strains

, physiological, and molecular differences in response to dietary restriction in three inbred mouse strains. Am J Physiol Endocrinol Metab 291: E574 -E581, 2006. First published May 2, 2006; doi:10.1152/ajpendo.00068.2006.-Food restriction paradigms are widely used in animal studies to investigate systems involved in energy regulation. We have observed behavioral, physiological, and molecular differences in response to food restriction in three inbred mouse strains, C57BL/6J, A/J, and DBA/2J. These are the progenitors of chromosome substitution and recombinant inbred mouse strains used for mapping complex traits. DBA/2J and A/J mice increased their locomotor activity during food restriction, and both displayed a decrease in body temperature, but the decrease was significantly larger in DBA/2J compared with A/J mice. C57BL/6J mice did not increase their locomotor activity and displayed a large decrease in their body temperature. The large decline in body temperature during food restriction in DBA/2J and C57BL/6J strains was associated with a robust reduction in plasma leptin levels. DBA/2J mice showed a marked decrease in white and brown adipose tissue masses and an upregulation of the antithermogenic hypothalamic neuropeptide Y Y1 receptor. In contrast, A/J mice showed a reduction in body temperature to a lesser extent that may be explained by downregulation of the thermogenic melanocortin 3 receptor and by behavioral thermoregulation as a consequence of their increased locomotor activity. These data indicate that genetic background is an important parameter in controlling an animal's adaptation strategy in response to food restriction. Therefore, mouse genetic mapping populations based on these progenitor lines are highly valuable for investigating mechanisms underlying strain-dependent differences in behavioral physiology that are seen during reduced food availability. locomotor activity; body temperature; food intake; neuropeptide Y; melanocortin ENERGY BALANCE is regulated by processes that influence food intake and energy expenditure. The main components of energy expenditure are metabolism and thermogenesis induced by exercise, cold, and diet, and these are regulated by the interaction of behavioral, physiological, and molecular mechanisms. Imbalances in energy state can result in health problems, such as malnutrition, eating disorders, or obesity Food restriction paradigms are widely used in animal studies to investigate mechanisms involved in the regulation of energy balance Behavioral thermoregulation is one of the mechanisms by which endothermic animals achieve and maintain a stable body temperature during times of food shortage In addition to behavioral thermogenesis, endothermic animals use autonomic mechanisms to regulate their core temperature (47). For example, brown adipose tissue (BAT)-mediated nonshivering thermogenesis is involved in heat production when animals are exposed to cold. Mitochondrial uncoupling proteins (UCPs) in the BAT generate heat by uncoupling oxidative phosphorylation, and, in mice, targeted inactivation of the gene coding for UCP1 leads to cold sensitivity (13). Leptin increases the thermogenesis in BAT by increasing UCP1 expression (48); therefore, decreased heat production resulting from hypoleptinemia could be associated with the increased locomotor activity seen in some inbred mice strains and rats in response to restricted feeding. Leptin's effects on the hypothalamic neuropeptide Y (NPY) and melanocortin systems have been implicated in the regulation of energy balance (56, 59). For example, selective NPY Y 1 and Y 5 receptor agonists increase food consumption and decrease circulating levels of thyroid hormones, showing that both receptors mediate the stimulatory effects of NPY on foo

Diet and Gastrointestinal Bypass–Induced Weight Loss: The Roles of Ghrelin and Peptide YY

OBJECTIVE-Bariatric surgery causes durable weight loss. Gut hormones are implicated in obesity pathogenesis, dietary failure, and mediating gastrointestinal bypass (GIBP) surgery weight loss. In mice, we determined the effects of diet-induced obesity (DIO), subsequent dieting, and GIBP surgery on ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). To evaluate PYY's role in mediating weight loss post-GIBP, we undertook GIBP surgery in PyyKO mice.RESEARCH DESIGN AND METHODS-Male C57BL/6 mice randomized to a high-fat diet or control diet were killed at 4-week intervals. DIO mice underwent switch to ad libitum low-fat diet (DIO-switch) or caloric restriction (CR) for 4 weeks before being killed. PyyKO mice and their DIO wild-type (WT) littermates underwent GIBP or sham surgery and were culled 10 days post-operatively. Fasting acyl-ghrelin, total PYY, active GLP-1 concentrations, stomach ghrelin expression, and colonic Pyy and glucagon expression were determined. Fasting and postprandial PYY and GLP-1 concentrations were assessed 30 days postsurgery in GIBP and sham pair-fed (sham.PF) groups.RESULTS-DIO progressively reduced circulating fasting acyl-ghrelin, PYY, and GLP-1 levels. CR and DIO-switch caused weight loss but failed to restore circulating PYY to weight-appropriate levels. After GIBP, WT mice lost weight and exhibited increased circulating fasting PYY and colonic Pyy and glucagon expression. In contrast, the acute effects of GIBP on body weight were lost in PyyKO mice. Fasting PYY and postprandial PYY and GLP-1 levels were increased in GIBP mice compared with sham.PF mice.CONCLUSIONS-PYY plays a key role in mediating the early weight loss observed post-GIBP, whereas relative PYY deficiency during dieting may compromise weight-loss attempts. Diabetes 60:810-818, 201

Molecular genetics studies on the regulation of body mass, food intake and energy metabolism in the mouse : a model for human anorexia nervosa

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Compulsivity in mouse strains homologous with chromosomes 7p and 15q linked tot obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is a severe anxiety disorder characterized by obsessions and compulsions. The core symptom of OCD is compulsivity, the inability to stop thinking or acting when you want to, despite being aware of the uselessness of the content or the adverse consequences. To initiate a systematic search for genetic mechanisms underlying the pathophysiology of compulsivity, a panel of chromosome substitution (CS) strains, derived from mice that suppress (C57BL/6J strain) or maintain (A/J strain) high levels of repetitive wheel running during 2 hr of daily limited food access, was screened for this compulsive behavior. Following the genetic screen, we found linkage between compulsive wheel running and mouse chromosomes 2, 6, and 7 that show overlap with recently identified human linkage regions for OCD on chromosomes 7p and 15q. In the overlapping (human/mouse) genomic region, the CRH receptor 2 (CRHR2) gene was tested in a human case-control study. An initial exploration in OCD cases versus controls failed to detect an association between four-candidate CRH2R SNP's within this homologous linkage region and OCD. Genetic fine mapping of compulsivity in mice provides new opportunities to reveal mechanisms underlying this significant psychiatric trai

Subject standardization, acclimatization, and sample processing affect gut hormone levels and appetite in humans

Background & Aims: Gut hormones represent attractive therapeutic targets for the treatment of obesity and type 2 diabetes. However, controversy surrounds the effects that adiposity, dietary manipulations, and bariatric surgery have on their circulating concentrations. We sought to determine whether these discrepancies are due to methodologic differences. Methods: Ten normal-weight males participated in a 4-way crossover study investigating whether fasting appetite scores, plasma acyl-ghrelin, active glucagon-like peptide-1 (GLP-1), and peptide YY3–36 (PYY3–36) levels are altered by study-induced stress, prior food consumption, and sample processing. Results: Study visit order affected anxiety, plasma cortisol, and temporal profiles of appetite and plasma PYY3–36, with increased anxiety and cortisol concentrations on the first study day. Plasma cortisol area under the curve (AUC) correlated positively with plasma PYY3–36 AUC. Despite a 14-hour fast, baseline hunger, PYY3–36 concentrations, temporal appetite profiles, PYY3–36 AUC, and active GLP-1 were affected by the previous evening's meal. Sample processing studies revealed that sample acidification and esterase inhibition are required when measuring acyl-ghrelin and dipeptidyl-peptidase IV inhibitor addition for active GLP-1. However, plasma PYY3–36 concentrations were unaffected by addition of dipeptidyl-peptidase IV. Conclusions: Accurate assessment of appetite, feeding behavior, and gut hormone concentrations requires standardization of prior food consumption and subject acclimatization to the study protocol. Moreover, because of the labile nature of acyl-ghrelin and active GLP-1, specialized sample processing needs to be undertaken

Peripheral activation of the Y2-receptor promotes secretion of GLP-1 and improves glucose tolerance

International audienceThe effect of peptide tyrosine–tyrosine (PYY) on feeding is well established but currently its role in glucose homeostasis is poorly defined. Here we show in mice, that intraperitoneal (ip) injection of PYY3-36 or Y2R agonist improves nutrient-stimulated glucose tolerance and enhances insulin secretion; an effect blocked by peripheral, but not central, Y2R antagonist administration. Studies on isolated mouse islets revealed no direct effect of PYY3-36 on insulin secretion. Bariatric surgery in mice, enterogastric anastomosis (EGA), improved glucose tolerance in wild-type mice and increased circulating PYY and active GLP-1. In contrast, in Pyy-null mice, post-operative glucose tolerance and active GLP-1 levels were similar in EGA and sham-operated groups. PYY3-36 ip increased hepato-portal active GLP-1 plasma levels, an effect blocked by ip Y2R antagonist. Collectively, these data suggest that PYY3-36 therefore acting via peripheral Y2R increases hepato-portal active GLP-1 plasma levels and improves nutrient-stimulated glucose tolerance

Identifying Predictors of Activity Based Anorexia Susceptibility in Diverse Genetic Rodent Populations

Animal studies are very useful in detection of early disease indicators and in unravelling the pathophysiological processes underlying core psychiatric disorder phenotypes. Early indicators are critical for preventive and efficient treatment of progressive psychiatric disorders like anorexia nervosa. Comparable to physical hyperactivity observed in anorexia nervosa patients, in the activity-based anorexia rodent model, mice and rats express paradoxical high voluntary wheel running activity levels when food restricted. Eleven inbred mouse strains and outbred Wistar WU rats were exposed to the activity-based anorexia model in search of identifying susceptibility predictors. Body weight, food intake and wheel running activity levels of each individual mouse and rat were measured. Mouse strains and rats with high wheel running activity levels during food restriction exhibited accelerated body weight loss. Linear mixed models for repeated measures analysis showed that baseline wheel running activity levels preceding the scheduled food restriction phase strongly predicted activity-based anorexia susceptibility (mice: Beta = -0.0158 (+/- 0.003 SE), P<0.0001; rats: Beta = -0.0242 (+/- 0.004 SE), P<0.0001) compared to other baseline parameters. These results suggest that physical activity levels play an important role in activity-based anorexia susceptibility in different rodent species with genetically diverse background. These findings support previous retrospective studies on physical activity levels in anorexia nervosa patients and indicate that pre-morbid physical activity levels could reflect an early indicator for disease severity