Molecular and Physiological Adaptations to Weight Perturbation in Mice

In this dissertation the following aspects of the physiology of the defense of body weight were explored: (1) whether levels (thresholds) of defended adiposity can be raised or lowered by environmental manipulation; (2) the physiological and molecular changes that mediate increased metabolic efficiency following weight loss, (3) leptin's role in setting the threshold; (4) the effects of ambient temperature on metabolic phenotypes of weight perturbed to assess whether torpor contributes to metabolic adaptation; and (5) whether changes in gut microbiota accompany changes in diet composition and/or body weight.;To assess whether the threshold for defended body weight could be increased or decreased by environmental manipulations (i.e. high fat diet & weight restriction), we identified bioenergetic, behavioral, and CNS structural responses of C57BL/6J in long term diet induced obese (DIO) male mice to weight reduction. We found that maintenance of a body weight 20% below that imposed by a high fat diet results in metabolic adaptation - energy expenditure below that expected for body mass and composition - and structural changes of synapses onto arcuate pro-opiomelanocortin (POMC) cell bodies. These changes are qualitatively and quantitatively similar to those observed in weight-reduced animals that were never obese, suggesting that the previously obese animals are now "defending" a higher body weight. Maintenance of a lower body weight for more than 3 months was not accompanied by remission of the increased metabolic efficiency. Thus, the consequence of long term elevation of body weight suggests an increase in defended body fat that does not abate with time.;Mice can enter torpor -- a state of decreased metabolic rate and concomitant decrease in body temperature -- as a defense mechanism in times of low caloric availability and/or decreased ambient room temperatures. Declines in circulating leptin concentrations and low ambient room temperature have both been implicated in the onset of torpor. To assess the effects of ambient room temperature and leptin concentrations on metabolic adaptation, we characterized C57BL/6J and leptin deficient (Lepob) mice following weight perturbation at both 22°C and 30°C ambients. Weight-reduced C57BL/6J mice show metabolic adaptation at both ambient temperatures and do not enter torpor whereas weight-reduced Lepob animals readily enter torpor at 22°C. This suggests that sufficiently high absolute leptin concentrations may impede the onset of torpor and that torpor itself does not contribute to metabolic adaptation in mice that have an intact leptin axis.;To assess whether hyperleptinemia per se was capable of increasing the threshold for defended body weight, leptin was infused by minipumps into C57BL/6J mice for 18 weeks and body weight and metabolic parameters were studied following cessation of leptin infusion. Leptin infused mice did not defend elevated body weights compared to PBS infused mice suggesting that leptin alone may not be capable of setting the threshold for body weight defense implying that other changes accompanying obesity (i.e. increased free fatty acids, endoplasmic reticulum stress and/or inflammation of leptin-sensitive neural areas) are implicated. A caveat and possible confound to this study is the possibility of antibody production against the exogenous leptin that could have drastically decreased the amount of bioavailable leptin in these mice. This experiment did not assess antibody production but subsequent studies should do so.;Finally, gut microbiota have been implicated in the regulation of body weight possibly by impacting insulin resistance, inflammation, and adiposity via interactions with epithelial and endocrine cells. We assessed changes in relative abundances of cecal microbiota in mice following sustained changes in body weight and diet composition. In diet-induced obese (DIO) mice, we find that weight reduction resulted in shifts in specific bacteria abundance (Akkermansia and Mucispirillum) and that these changes were correlated with leptin concentrations. Leptin modulates mucin production in the gut possibly altering local microniches for certain bacteria providing a functional link between adiposity and gut-specific changes in bacterial populations. (Abstract shortened by UMI.)...