scholarly journals MetAP2 inhibition reduces food intake and body weight in a ciliopathy mouse model of obesity

2019 ◽  
Author(s):  
Tana S. Pottorf ◽  
Micaella Fagan ◽  
Bryan Burkey ◽  
David J. Cho ◽  
James E. Vath ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Mouse Model ◽  
Reduce Food Intake ◽  
Reduced Body ◽  
Conditional Deletion ◽  
Daily Food ◽  
Liver Morphology ◽  
Metabolic Indices ◽  
Preclinical And Clinical Studies

AbstractThe ciliopathies Bardet-Biedl Syndrome and Alström Syndrome are genetically inherited pleiotropic disorders with primary clinical features of hyperphagia and obesity. Methionine aminopeptidase 2 inhibitors (MetAP2i) have been shown in preclinical and clinical studies to reduce food intake, body weight, and adiposity. Here we investigated the effects of MetAP2i administration in a mouse model of ciliopathy produced by conditional deletion of the Thm1 gene in adulthood (Thm1 cko). Thm1 cko mice show decreased hypothalamic pro-opiomelanocortin expression as well as hyperphagia, obesity, metabolic disease and hepatic steatosis. In obese Thm1 cko mice, two-week administration of MetAP2i reduced daily food intake and reduced body weight 17.1% from baseline (vs. 5% reduction for vehicle). This was accompanied with decreased levels of blood glucose, insulin and leptin. Further, MetAP2i reduced gonadal adipose depots and adipocyte size and improved liver morphology. This is the first report of MetAP2i reducing hyperphagia and body weight, and ameliorating metabolic indices in a mouse model of ciliopathy. These results support further investigation of MetAP2 inhibition as a potential therapeutic strategy for ciliary-mediated forms of obesity.

scholarly journals Effects of estradiol and progesterone on food intake, body weight, and carcass adiposity in weanling rats

1981 ◽  
Vol 240 (5) ◽  
pp. E499-E503 ◽  
Author(s):  
S. M. Schwartz ◽  
G. N. Wade
Keyword(s):  
Body Weight ◽  
Adipose Tissue ◽  
Weight Gain ◽  
Food Intake ◽  
Body Weight Gain ◽  
Estradiol Benzoate ◽  
Female Rats ◽  
Reduce Food Intake ◽  
Reduced Body ◽  
Adipose Tissue Lipoprotein Lipase

The effects of estradiol and progesterone on food intake, body weight, carcass adiposity, and adipose tissue lipoprotein lipase (LPL) activity were investigated in weanling female rats. Treatment with estradiol benzoate (EB) reduced body weight gain in ovariectomized (OVX) weanlings as it does in adults. However, other responses to EB were attenuated or absent in weanlings. EB treatment did not reduce food intake, carcass adiposity, or adipose tissue LPL activity. This impaired responsiveness to EB may be due to decreased levels of cytoplasmic estrogen receptors in liver and adipose tissue (but not hypothalamus) in weanlings. On the other hand, responsiveness to progesterone was adultlike in weanlings. Treatment of OVX, EB-primed weanlings with progesterone increased food intake, body weight gain, and carcass adiposity. This adultlike responsiveness to progesterone was associated with adultlike levels of adipose tissue progestin receptors. However, progesterone treatment did not increase adipose tissue LPL activity in weanlings, indicating that changes in LPL activity are not necessary for progesterone-induced obesity.

scholarly journals Multiple cycles of repeated treatments with a Phaseolus vulgaris dry extract reduce food intake and body weight in obese rats

2011 ◽  
Vol 106 (5) ◽  
pp. 762-768 ◽  
Author(s):  
Mauro A. M. Carai ◽  
Noemi Fantini ◽  
Barbara Loi ◽  
Giancarlo Colombo ◽  
Gian Luigi Gessa ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Phaseolus Vulgaris ◽  
Treatment Phase ◽  
Reduce Food Intake ◽  
Dry Extract ◽  
Daily Food Intake ◽  
Daily Food ◽  
Multiple Cycles ◽  
Dose Dependent

Previous lines of experimental evidence have suggested that Phaseolus vulgaris extracts reduce food intake, body weight, lipid accumulation, hedonic properties of food, carbohydrate absorption and metabolism, and glycaemia in rats. The present study was designed to assess the effect of multiple cycles of repeated treatments with a standardised P. vulgaris dry extract on daily food intake and body weight in genetically obese Zucker fa/fa rats (Expt 1). Additionally, the study tested the effect of acute treatment with P. vulgaris dry extract on postprandial glycaemia in Zucker fa/fa rats (Expt 2). In Expt 1, P. vulgaris dry extract was administered daily, at doses of 50 and 500 mg/kg, in three 5 d treatment periods followed by three 20 d off-treatment periods. Administration of P. vulgaris dry extract resulted in dose-dependent decreases in daily food intake and body weight in each treatment phase. Reductions in food intake were of comparable magnitude in each treatment phase. In Expt 2, food-deprived rats were acutely treated with 50 and 500 mg P. vulgaris dry extract per kg immediately before access to a fixed amount of a starch-enriched chow. Treatment with P. vulgaris dry extract resulted in a dose-dependent suppression of glycaemia. These results extend previous data on the anorectic and hypoglycaemic effects of the P. vulgaris dry extract to a validated animal model of obesity. Together with data published previously in the literature, these results strengthen the hypothesis that potentially effective, novel pharmacotherapies for obesity and related disorders may originate from extracts and derivatives of P. vulgaris.

Methylnaltrexone reduced body weight gain in ob/ob mice

2018 ◽  
Vol 5 (4) ◽  
pp. 213 ◽  
Author(s):  
Chun-Su Yuan, MD, PhD ◽  
Chong-Zhi Wang, PhD ◽  
Anoja Attele, MD ◽  
Liu Zhang, PhD
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Body Weight Gain ◽  
Day Treatment ◽  
Clinical Importance ◽  
The Body ◽  
Control Group ◽  
Weight Changes ◽  
Reduced Body ◽  
Daily Food

Objective: Opioids may function to regulate food intake and body weight, an activity that could be predominantly centrally mediated. In this study, the authors evaluated the effects of a peripherally acting opioid receptor antagonist, methylnaltrexone, on weight changes in adult obese ob/ob mice.Results: After a 12-day treatment with naloxone 0.3 mg/kg, weight was reduced from 63.7 ± 1.1 g in the control group to 59.2 ± 0.9 g in the naloxone group (p < 0.05). After a 12-day treatment with methylnaltrexone 3.0 mg/kg, weight increase completely ceased. The body weight was 63.9 ± 1.0 g in the control group when compared with 55.9 ± 1.2 g in the drug group (p < 0.01). The effect of methylnaltrexone (1.0 mg to 3.0 mg/kg) on weight changes was dose-dependent (p < 0.01). Methylnaltrexone significantly reduced daily food intake (p < 0.05), but did not affect body temperature and energy expenditure. Using HPLC analysis, no detectable naltrexone levels were found in association with methylnaltrexone administration. Whether the observed methylnaltrexone effects are primarily related to the antagonism of endorphinergic system remains to be investigated.Conclusions: Our results suggest that the peripheral opioid mechanism contributes to modulating food ingestion and methylnaltrexone may have clinical importance in obesity management.

scholarly journals A Comparative Study of the Central Effects of Specific Proopiomelancortin (POMC)-Derived Melanocortin Peptides on Food Intake and Body Weight in Pomc Null Mice

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 5940-5947 ◽  
Author(s):  
Y. C. Loraine Tung ◽  
Sarah J. Piper ◽  
Debra Yeung ◽  
Stephen O’Rahilly ◽  
Anthony P. Coll
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Lean Mass ◽  
Energy Homeostasis ◽  
Reduce Food Intake ◽  
Dark Cycle ◽  
Short Term ◽  
Reduced Body ◽  
Melanocortin Peptides ◽  
Anorexigenic Effect

Functional disruption of either MC3R or MC4R results in obesity, implicating both in the control of energy homeostasis. The ligands for these receptors are derived from the prohormone proopiomelancortin (POMC), which is posttranslationally processed to produce a set of melanocortin peptides with a range of activities at the MC3R and MC4R. The relative importance of each of these peptides α-MSH, γ3-MSH, γ2-MSH, γ-lipotropin (γ-LPH) and, in man but not in rodents, β-MSH] in the maintenance of energy homeostasis is, as yet, unclear. To investigate this further, equimolar amounts (2 nmol) of each peptide were centrally administered to freely feeding, corticosterone-supplemented, Pomc null (Pomc−/−) mice. After a single dose at the onset of the dark cycle, α-MSH had the most potent anorexigenic effect, reducing food intake to 35% of sham-treated animals. β-MSH, γ-LPH, and γ3- and γ2-MSH all reduced food intake but to a lesser degree. The effects of peptide administration over 3 d were also assessed. Only α-MSH significantly reduced body weight, affecting both fat and lean mass. Other peptides had no significant effect on body weight. Pair-feeding of sham-treated mice to those treated with α-MSH resulted in identical changes in total weight, fat and lean mass indicating that the effects of α-MSH were primarily due to reduced food intake rather than increased energy expenditure. Although other melanocortins can reduce food intake in the short-term, only α-MSH can reduce the excess fat and lean mass found in Pomc−/− mice, mediated largely through an effect on food intake.

Serum leptin concentration in pigs selected for high or low daily food intake

2000 ◽  
Vol 2000 ◽  
pp. 22-22
Author(s):  
N.D. Cameron ◽  
J.C. Penman ◽  
E. McCullough
Keyword(s):  
Food Intake ◽  
Recessive Gene ◽  
Blood Stream ◽  
Correlated Response ◽  
Reduce Food Intake ◽  
Large White ◽  
Daily Food Intake ◽  
Gene Coding ◽  
Daily Food ◽  
Seven Generations

Leptin is synthesised and secreted from adipocytes into the blood stream and transported to the brain, where it acts to cause a release of factors which can reduce food intake (Houseknecht et al., 1998). There are two murine mutations of the recessive gene coding for leptin which are associated with obesity. The Lepob allele determines synthesis and secretion of leptin, while the Lepdb allele determines responsiveness to leptin. In the Edinburgh lean growth experiment in pigs, selection for high and low daily food intake (DFI) has been practiced for seven generations in a Large White herd, which provides the experimental resource to determine if the correlated response in fat deposition is consistent with insufficient leptin production or with insensitivity to leptin.

scholarly journals Antiobesity Effects of the β-Cell Hormone Amylin in Diet-Induced Obese Rats: Effects on Food Intake, Body Weight, Composition, Energy Expenditure, and Gene Expression

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 5855-5864 ◽  
Author(s):  
Jonathan D. Roth ◽  
Heather Hughes ◽  
Eric Kendall ◽  
Alain D. Baron ◽  
Christen M. Anderson
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Energy Expenditure ◽  
Respiratory Quotient ◽  
Metabolic Effects ◽  
Mrna Levels ◽  
Lean Tissue ◽  
Reduced Body ◽  
Diet Induced Obesity ◽  
Cell Hormone

Effects of amylin and pair feeding (PF) on body weight and metabolic parameters were characterized in diet-induced obesity-prone rats. Peripherally administered rat amylin (300 μg/kg·d, 22d) reduced food intake and slowed weight gain: approximately 10% (P &lt; 0.05), similar to PF. Fat loss was 3-fold greater in amylin-treated rats vs. PF (P &lt; 0.05). Whereas PF decreased lean tissue (P &lt; 0.05 vs. vehicle controls; VEH), amylin did not. During wk 1, amylin and PF reduced 24-h respiratory quotient (mean ± se, 0.82 ± 0.0, 0.81 ± 0.0, respectively; P &lt; 0.05) similar to VEH (0.84 ± 0.01). Energy expenditure (EE mean ± se) tended to be reduced by PF (5.67 ± 0.1 kcal/h·kg) and maintained by amylin (5.86 ± 0.1 kcal/h·kg) relative to VEH (5.77 ± 0.0 kcal/h·kg). By wk 3, respiratory quotient no longer differed; however, EE increased with amylin treatment (5.74 ± 0.09 kcal/·kg; P &lt; 0.05) relative to VEH (5.49 ± 0.06) and PF (5.38 ± 0.07 kcal/h·kg). Differences in EE, attributed to differences in lean mass, argued against specific amylin-induced thermogenesis. Weight loss in amylin and pair-fed rats was accompanied by similar increases arcuate neuropeptide Y mRNA (P &lt; 0.05). Amylin treatment, but not PF, increased proopiomelanocortin mRNA levels (P &lt; 0.05 vs. VEH). In a rodent model of obesity, amylin reduced body weight and body fat, with relative preservation of lean tissue, through anorexigenic and specific metabolic effects.

Effects of intermittent intraperitoneal infusion of salmon calcitonin on food intake and adiposity in obese rats

2007 ◽  
Vol 293 (5) ◽  
pp. R1798-R1808 ◽  
Author(s):  
Prasanth K. Chelikani ◽  
Alvin C. Haver ◽  
Roger D. Reidelberger
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Salmon Calcitonin ◽  
Chronic Administration ◽  
Inhibitory Effect ◽  
Free Access ◽  
Daily Food Intake ◽  
Intraperitoneal Infusion ◽  
Daily Food ◽  
Obese Rats

Chronic administration of anorexigenic substances to experimental animals by injections or continuous infusion typically produces no effect or a transient reduction in daily food intake and body weight. Our aim was to identify an intermittent dosing strategy for intraperitoneal infusion of salmon calcitonin (sCT), a homolog of amylin that produces a sustained 25–35% reduction in daily food intake and adiposity in diet-induced obese rats. Rats (649 ± 10 g body wt, 27 ± 1% body fat), with intraperitoneal catheters tethered to infusion swivels, had free access to a 45% fat diet. Food intake, body weight, and adiposity during the 7-wk test period were relatively stable in the vehicle-treated rats ( n = 16). None of 10 sCT dosing regimens administered in succession to a second group of rats ( n = 18) produced a sustained 25–35% reduction in daily food intake for >5 days, although body weight and adiposity were reduced by 9% (587 ± 12 vs. 651 ± 14 g) and 22% (20.6 ± 1.2 vs. 26.5 ± 1.1%), respectively, across the 7-wk period. The declining inhibitory effect of sCT on daily food intake with the 6-h interinfusion interval appeared to be due in part to an increase in food intake between infusions. The declining inhibitory effect of sCT on daily food intake with the 2- to 3-h interinfusion interval suggested possible receptor downregulation and tolerance to frequent sCT administration; however, food intake increased dramatically when sCT was discontinued for 1 day after apparent loss of treatment efficacy. Together, these results demonstrate the activation of a potent homeostatic response to increase food intake when sCT reduces food intake and energy reserves in diet-induced obese rats.

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