Effects of leptin replacement alone and with exendin-4 on food intake and weight regain in weight-reduced diet-induced obese rats.
Bibliographic record
Abstract
Reidelberger R, Haver A, Chelikani PK, Apenteng B, Perriotte-Olson C, Anders K, Steenson S, Blevins JE. Effects of leptin replacement alone and with exendin-4 on food intake and weight regain in weight-reduced diet-induced obese rats. Am J Physiol Endocrinol Metab 302: E1576–E1585, 2012. First published April 17, 2012; doi:10.1152/ajpendo.00058.2012.—Weight loss in obese humans produces a relative leptin deficiency, which is postulated to activate potent orexigenic and energy conservation mechanisms to restrict weight loss and promote weight regain. Here we determined whether leptin replacement alone or with GLP-1 receptor agonist exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced diet-induced obese (DIO) rats. Forty percent restriction in daily intake of a high-fat diet in DIO rats for 4 wk reduced body weight by 12%, body fat by 29%, and plasma leptin by 67% and normalized leptin sensitivity. When food restriction ended, body weight, body fat, and plasma leptin increased rapidly. Daily administration of leptin [3-h intraperitoneal (ip) infusions (4 nmol·kg-1·h-1)] at onset and end of dark period for 3 wk did not attenuate hyperphagia and weight regain, nor did it affect mean daily meal sizes or meal numbers. Exendin-4 (50 pmol·kg-1·h-1) infusions during the same intervals prevented postrestriction hyperphagia and weight regain by normalizing meal size. Coadministration of leptin and exendin-4 did not reduce body weight more than exendin-4 alone. Instead, leptin began to attenuate the inhibitory effects of exendin-4 on food intake, meal size, and weight regain by the end of the second week of administration. Plasma leptin in rats receiving leptin was sevenfold greater than in rats receiving vehicle and 17-fold greater than in rats receiving exendin-4. Together, these results do not support the hypothesis that leptin replacement alone or with exendin-4 attenuates weight regain or promotes greater weight loss in weight-reduced DIO rats. OBESITY IS A CHRONIC, stigmatized, and costly disease that is rarely curable and is increasing in prevalence in most of the world (4). Current therapies for producing weight loss in obese individuals, i.e., dieting, exercise, and medications, are woefully ineffective in producing long-term weight loss. This is likely due to redundancy and plasticity in the complex physiological system that controls food intake and regulates energy reserves. Many experts believe that multidrug therapy aimed at different components of this regulatory system will be required to produce a significant reduction in adiposity (4, 13, 21, 22). An important early step in the development of antiobesity drugs is determining whether chronic administration of anorexigenic substances, alone or in combination, can produce a prolonged decrease in daily food intake and adiposity in experimental animals. Methods of administration usually include daily injections or insertion of an osmotic minipump beneath the skin or into the peritoneal cavity to deliver substances continuously for 1 wk or more. Treatments typically produce only transient decreases in food intake, resulting in relatively small or no decreases in body weight and adiposity (e.g., see Refs. 16, 28, 38, 43, and 44). Likely reasons include development of a compensatory increase in food intake between injections, desensitization and downregulation of receptors in response to continuous or frequent administration of high doses, and weight loss-induced activation of counteracting orexigenic and energy conservation mechanisms to restore energy reserves (14, 24, 37, 39).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".