scholarly journals Three weeks of postweaning exercise in DIO rats produces prolonged increases in central leptin sensitivity and signaling

2009 ◽  
Vol 296 (3) ◽  
pp. R537-R548 ◽  
Author(s):  
Christa M. Patterson ◽  
Sebastien G. Bouret ◽  
Ambrose A. Dunn-Meynell ◽  
Barry E. Levin
Keyword(s):  
Food Intake ◽  
Receptor Binding ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
High Energy ◽  
Decrease Food Intake ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity

In rats selectively bred to develop diet-induced obesity (DIO) 3 wk of postweaning exercise reduces weight and adipose regain for 10 wk after exercise cessation, despite intake of 31% fat high-energy (HE) diet. To test the hypothesis that this effect is due to increased central leptin sensitivity, 4-wk-old DIO rats were fed the HE diet and left sedentary (Sed), exercised for 3 wk, and then remained sedentary for 10 additional weeks (Ex/Sed) or continued exercise for a full 13 wk (Ex). After 3 wk, leptin (5 mg/kg ip) induced a 36% decrease in 24-h food intake in Ex rats, while Sed rats had no change in 24-h intake. Ex rats also had 23% more leptin-induced phospho-STAT3 (pSTAT3)-expressing neurons in the arcuate nucleus (ARC) and 95% and 68% higher 125I-labeled leptin receptor binding in the ventromedial and dorsomedial nuclei than did Sed rats, respectively. At 7 wk after onset, leptin decreased 24-h intake by 20% in Ex and 24% in Ex/Sed rats without altering Sed intake. After a total of 13 wk, compared with Sed rats, Ex and Ex/Sed rats had 58% and 38% less fat, respectively, but leptin failed to decrease food intake in any group. Nevertheless, Ex, but not Ex/Sed rats, still had 32% more ARC leptin-induced pSTAT3-expressing neurons than Sed rats. These data suggest that brief postweaning exercise in DIO rats that are inherently leptin resistant causes a sustained resistance to obesity on HE diet, which is, in part, due to increased central leptin sensitivity.

Ontogeny of diet-induced obesity in selectively bred Sprague-Dawley rats

2003 ◽  
Vol 285 (3) ◽  
pp. R610-R618 ◽  
Author(s):  
Matthew R. Ricci ◽  
Barry E. Levin
Keyword(s):  
Leptin Receptor ◽  
Splice Variants ◽  
Caloric Intake ◽  
High Energy ◽  
Sprague Dawley ◽  
Low Fat Diet ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
Sprague Dawley Rats ◽  
Plasma Leptin

Outbred Sprague-Dawley rats selectively bred for their propensity to develop diet-induced obesity (DIO) become heavier on low-fat diet than those bred to be diet resistant (DR) beginning at ∼5 wk of age. Here we assessed the development of metabolic and neural functions for insights into the origins of their greater weight gain. From week 5 to week 10, chow-fed DIO rats gained 15% more body weight and ate ∼14% more calories but had only slightly greater adiposity and plasma leptin than DR rats. From day 3 through week 10, DIO and DR rats had similar mRNA expression of arcuate nucleus neuropeptide Y, proopiomelanocortin, agouti-related peptide, and all splice variants of the leptin receptor (OB-R). When fed a high-energy (HE; 31% fat) diet, 7-wk-old DIO rats had a 240% increase in plasma leptin levels after only 3 days. Despite this early leptin rise, they maintained a persistent hyperphagia and became more obese than chow-fed DIO rats and DR rats fed chow or HE diet. Their failure to reduce caloric intake, despite high levels of leptin, suggests that selectively bred DIO rats might have reduced leptin sensitivity similar to that seen in the outbred DIO parent strain.

Abnormalities of leptin and ghrelin regulation in obesity-prone juvenile rats

2003 ◽  
Vol 285 (5) ◽  
pp. E949-E957 ◽  
Author(s):  
Barry E. Levin ◽  
Ambrose A. Dunn-Meynell ◽  
Matt R. Ricci ◽  
David E. Cummings
Keyword(s):  
Body Weight ◽  
Mrna Expression ◽  
Leptin Receptor ◽  
High Energy ◽  
Proximate Cause ◽  
Ghrelin Receptor ◽  
Insulin Levels ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
Hypothalamic Nuclei

Rats selectively bred to develop diet-induced obesity (DIO) spontaneously gain more body weight between 5 and 7 wk of age than do those bred to be diet resistant (DR). Here, chow-fed DIO rats ate 9% more and gained 19% more body weight from 5 to 6 wk of age than did DR rats but had comparable leptin and insulin levels. However, 6-wk-old DIO rats had 29% lower plasma ghrelin levels at dark onset but equivalent levels 6 h later compared with DR rats. When subsequently fed a high-energy (HE; 31% fat) diet for 10 days, DIO rats ate 70% more, gained more body and adipose depot weight, had higher leptin and insulin levels, and had 22% lower feed efficiency than DR rats fed HE diet. In DIO rats on HE diet, leptin levels increased significantly at 3 days followed by increased insulin levels at 7 days. These altered DIO leptin and ghrelin responses were associated with 10% lower leptin receptor mRNA expression in the arcuate (ARC), dorsomedial (DMN), and ventromedial hypothalamic nuclei and 13 and 15% lower ghrelin receptor (GHS-R) mRNA expression in the ARC and DMN than in the DR rats. These data suggest that increased ghrelin signaling is not a proximate cause of DIO, whereas reduced leptin sensitivity might play a causal role.

scholarly journals Large Litter Rearing Enhances Leptin Sensitivity and Protects Selectively Bred Diet-induced Obese Rats from Becoming Obese

2010 ◽  
Vol 31 (4) ◽  
pp. 600-601 ◽  
Author(s):  
Christa M. Patterson ◽  
Sebastien G. Bouret ◽  
Sunny Park ◽  
Boman G. Irani ◽  
Ambrose A. Dunn-Meynell ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Paraventricular Nucleus ◽  
Receptor Binding ◽  
Leptin Receptor ◽  
Body Weight Gain ◽  
High Energy ◽  
Leptin Resistance ◽  
Leptin Sensitivity ◽  
Plasma Leptin

Abstract Because rearing rats in large litters (LLs) protects them from becoming obese, we postulated that LL rearing would protect rats selectively bred to develop diet-induced obesity (DIO) from becoming obese by overcoming their inborn central leptin resistance. Male and female DIO rats were raised in normal litters (10 pups/dam) or LLs (16 pups/dam) and assessed for anatomical, biochemical, and functional aspects of leptin sensitivity at various ages when fed low-fat chow or a 31% fat high-energy (HE) diet. LL rearing reduced plasma leptin levels by postnatal d 2 (P) 2 and body weight gain by P8. At P16, LL DIO neonates had increased arcuate nucleus (ARC) binding of leptin to its extracellular receptors and at P28 an associated increase of their agouti-related peptide and α-MSH axonal projections to the paraventricular nucleus. Reduced body weight persisted and was associated with increased ARC leptin receptor binding and sensitivity to the anorectic effects of leptin, reduced adiposity, and enhanced insulin sensitivity in LL DIO rats fed chow until 10 wk of age. The enhanced ARC leptin receptor binding and reduced adiposity of LL DIO rats persisted after an additional 5 wk on the HE diet. Female LL DIO rats had similar reductions in weight gain on both chow and HE diet vs. normal litter DIO rats. We postulate that LL rearing enhances DIO leptin sensitivity by lowering plasma leptin levels and thereby increasing leptin receptor availability and that this both enhances the ARC-paraventricular nucleus pathway development and protects them from becoming obese.

Reduced central leptin sensitivity in rats with diet-induced obesity

2002 ◽  
Vol 283 (4) ◽  
pp. R941-R948 ◽  
Author(s):  
Barry E. Levin ◽  
Ambrose A. Dunn-Meynell
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Food Restriction ◽  
Arcuate Nucleus ◽  
High Energy ◽  
Chow Diet ◽  
Diet Induced Obesity ◽  
Leptin Sensitivity ◽  
Ad Libitum ◽  
Plasma Leptin

On low-fat chow diet, rats prone to diet-induced obesity (DIO) have increased arcuate nucleus neuropeptide Y (NPY) expression but similar leptin levels compared with diet-resistant (DR) rats (19). Here, body weight and leptin levels rose in DIO rats, and they defended their higher body weight after only 1 wk on a 31% fat high-energy (HE) diet. However, DIO NPY expression did not fall to DR levels until 4 wk when plasma leptin was 168% of DR levels. When switched to chow, DIO rats lost carcass fat (18). By 10 wk, leptin levels fell to 148% and NPY expression again rose to 150% of DR levels. During 4 wk of food restriction, DIO leptin fell by ∼50% while NPY increased by 30%. While both returned to control levels by 8 wk, DIO rats still regained all lost weight when fed ad libitum. Finally, the anorexic effect of intracerebroventricular leptin (10 μg) was inversely correlated with subsequent 3-wk weight gain on HE diet. Thus NPY expression and food intake are less sensitive to the leptin's suppressive effects in DIO rats. While this may predispose them to develop DIO, it does not fully explain their defense of a higher body weight on HE diet.

Influence of photoperiod and gonadal status on food intake, adiposity, and gene expression of hypothalamic appetite regulators in a seasonal mammal

2007 ◽  
Vol 292 (1) ◽  
pp. R242-R252 ◽  
Author(s):  
Chantacha Anukulkitch ◽  
Alexandra Rao ◽  
Frank R. Dunshea ◽  
Dominique Blache ◽  
Gerald A. Lincoln ◽  
...  
Keyword(s):  
Gene Expression ◽  
Food Intake ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Reproductive Axis ◽  
Pomc Gene ◽  
Gonadal Status ◽  
Long Photoperiod ◽  
Refractory Phase

We studied the effects of photoperiod on metabolic profiles, adiposity, and gene expression of hypothalamic appetite-regulating peptides in gonad-intact and castrated Soay rams. Groups of five to six animals were studied 6, 18, or 30 wk after switching from long photoperiod (LP: 16 h of light) to short photoperiod (SP: 8 h of light). Reproductive and metabolic indexes were measured in blood plasma. Expression of neuropeptide Y (NPY), proopiomelanocortin (POMC), and leptin receptor (ObRb) in the arcuate nucleus was measured using in situ hybridization. Testosterone levels of intact animals were low under LP, increased to a peak at 16 wk under SP, and then declined. Voluntary food intake (VFI) was high under LP in both intact and castrated animals, decreased to a nadir at 12–16 wk under SP, and then recovered, but only in intact rams as the reproductive axis became photorefractory to SP. NPY gene expression varied positively and POMC expression varied negatively with the cycle in VFI, with differences between intact and castrate rams in the refractory phase. ObRb expression decreased under SP, unrelated to changes in VFI. Visceral fat weight also varied between the intact and castrated animals across the cycle. We conclude that 1) photoperiodic changes in VFI reflect changes in NPY and POMC gene expression, 2) changes in ObRb gene expression are not necessarily determinants of changes in VFI, 3) gonadal status affects the pattern of VFI that changes with photoperiod, and 4) in the absence of gonadal factors, animals can eat less but gain adiposity.

Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset

2004 ◽  
Vol 286 (1) ◽  
pp. R143-R150 ◽  
Author(s):  
Barry E. Levin ◽  
Ambrose A. Dunn-Meynell ◽  
William A. Banks
Keyword(s):  
Blood Brain Barrier ◽  
Leptin Receptor ◽  
Nucleus Tractus Solitarius ◽  
High Energy ◽  
Brain Barrier ◽  
Leptin Signaling ◽  
Caloric Density ◽  
Diet Induced Obesity ◽  
Blood Brain ◽  
Arcuate Nuclei

Rats selectively bred to develop diet-induced obesity (DIO) were compared with those bred to be diet resistant (DR) on a 31% fat high-energy diet with regard to their central leptin signaling and blood-brain barrier (BBB) transport. Peripheral leptin injection (15 mg/kg ip) into lean 4- to 5-wk-old rats produced 54% less anorexia in DIO than DR rats. DIO rats also had 21, 63, and 64% less leptin-induced immunoreactive phosphorylated signal transducer and activator of transcription 3 (pSTAT3) expression in the hypothalamic arcuate, ventromedial, and dorsomedial nuclei, respectively. However, hindbrain leptin-induced nucleus tractus solitarius pSTAT3 and generalized sympathetic (24-h urine norepinephrine) activation were comparable. Reduced central leptin signaling was not due to defective BBB transport since transport did not differ between lean 4- to 5-wk-old DIO and DR rats. Conversely, DIO leptin BBB transport was reduced when they became obese at 23 wk of age on low-fat chow or after 6 wk on high-energy diet. In addition, leptin receptor mRNA expression was 23% lower in the arcuate nuclei of 4- to 5-wk-old DIO compared with DR rats. Thus a preexisting reduction in hypothalamic but not brain stem leptin signaling might contribute to the development of DIO when dietary fat and caloric density are increased. Defects in leptin transport appear to be an acquired defect associated with the development of obesity and possibly age.

scholarly journals Diet-induced obesity impairs mammary development and lactogenesis in murine mammary gland

2005 ◽  
Vol 288 (6) ◽  
pp. E1179-E1187 ◽  
Author(s):  
David J. Flint ◽  
Maureen T. Travers ◽  
Michael C. Barber ◽  
Nadine Binart ◽  
Paul A. Kelly
Keyword(s):  
Mammary Gland ◽  
Food Intake ◽  
De Novo ◽  
Acid Synthesis ◽  
High Energy ◽  
Mammary Development ◽  
Active State ◽  
Total Enzyme Activity ◽  
Diet Induced Obesity ◽  
Secretion Expression

We have developed a mouse model of diet-induced obesity that shows numerous abnormalities relating to mammary gland function. Animals ate ∼40% more calories when offered a high-fat diet and gained weight at three times the rate of controls. They exhibited reduced conception rates, increased peripartum pup mortality, and impaired lactogenesis. The impairment of lactogenesis involved lipid accumulation in the secretory epithelial cells indicative of an absence of copius milk secretion. Expression of mRNAs for β-casein, whey acid protein, and α-lactalbumin were all decreased immediately postpartum but recovered as lactation was established over 2–3 days. Expression of acetyl-CoA carboxylase (ACC)-α mRNA was also decreased at parturition as was the total enzyme activity, although there was a compensatory increase in the proportion in the active state. By day 10 of lactation, the proportion of ACC in the active state was also decreased in obese animals, indicative of suppression of de novo fatty acid synthesis resulting from the supply of preformed fatty acids in the diet. Although obese animals consumed more calories in the nonpregnant and early pregnant states, they showed a marked depression in fat intake around day 9 of pregnancy before food intake recovered in later pregnancy. Food intake increased dramatically in both lean and obese animals during lactation although total calories consumed were identical in both groups. Thus, despite access to high-energy diets, the obese animals mobilized even more adipose tissue during lactation than their lean counterparts. Obese animals also exhibited marked abnormalities in alveolar development of the mammary gland, which may partially explain the delay in differentiation evident during lactogenesis.

scholarly journals Leptin Sensitivity in the Developing Rat Hypothalamus

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 6073-6082 ◽  
Author(s):  
A.-S. Carlo ◽  
M. Pyrski ◽  
C. Loudes ◽  
A. Faivre-Baumann ◽  
J. Epelbaum ◽  
...  
Keyword(s):  
Food Intake ◽  
Neuropeptide Y ◽  
Leptin Receptor ◽  
Primary Cultures ◽  
Cytokine Signaling ◽  
Neuronal Cultures ◽  
Mrna Levels ◽  
Leptin Signaling ◽  
Leptin Sensitivity

In adults, the adipocyte-derived hormone, leptin, regulates food intake and body weight principally via the hypothalamic arcuate nucleus (ARC). During early postnatal development, leptin functions to promote the outgrowth of neuronal projections from the ARC, whereas a selective insensitivity to the effects of leptin on food intake appears to exist. To investigate the mechanisms underlying the inability of leptin to regulate food intake during early development, leptin signaling was analyzed both in vitro using primary cultures of rat embryonic ARC neurones and in vivo by challenging early postnatal rats with leptin. In neuronal cultures, despite the presence of key components of the leptin signaling pathway, no detectable activation of either signal transducer and activator of transcription 3 or the MAPK pathways by leptin was detected. However, leptin down-regulated mRNA levels of proopiomelanocortin and neuropeptide Y and decreased somatostatin secretion. Leptin challenge in vivo at postnatal d (P) 7, P14, P21, and P28 revealed that, in contrast to adult and P28 rats, mRNA levels of neuropeptide Y, proopiomelanocortin, agouti-related peptide and cocaine- and amphetamine-regulated transcript were largely unaffected at P7, P14, and P21. Furthermore, leptin stimulation increased the suppressor of cytokine signaling-3 mRNA levels at P14, P21, and P28 in several hypothalamic nuclei but not at P7, indicating that selective leptin insensitivity in the hypothalamus is coupled to developmental shifts in leptin receptor signaling. Thus, the present study defines the onset of leptin sensitivity in the regulation of energy homeostasis in the developing hypothalamus.

scholarly journals Silencing of OB-RGRP in mouse hypothalamic arcuate nucleus increases leptin receptor signaling and prevents diet-induced obesity

2007 ◽  
Vol 104 (49) ◽  
pp. 19476-19481 ◽  
Author(s):  
C. Couturier ◽  
C. Sarkis ◽  
K. Seron ◽  
S. Belouzard ◽  
P. Chen ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Receptor Signaling ◽  
Diet Induced Obesity ◽  
Hypothalamic Arcuate Nucleus

scholarly journals Xiaoyaosan Decoction Regulates Changes in Neuropeptide Y and Leptin Receptor in the Rat Arcuate Nucleus after Chronic Immobilization Stress

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Shao-Xian Wang ◽  
Jia-Xu Chen ◽  
Guang-Xin Yue ◽  
Ming-Hua Bai ◽  
Mei-Jing Kou ◽  
...  
Keyword(s):  
Weight Loss ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Chronic Stress ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Bodyweight Loss ◽  
Stress Group ◽  
Regulatory Effects ◽  
Neuroendocrine Mechanism

The arcuate nucleus (ARC) in the basal of hypothalamus plays an important role in appetite regulation and energy balance. We sought to investigate the central neuroendocrine mechanism of appetite decrease and weight loss under chronic stress by observing the regulatory effects of Xiaoyaosan decoction in the expression of leptin receptor (ob-R) and neuropeptide Y (NPY) in the ARC. Our results showed that bodyweight and food intake of rats in the 21-day stress group increased slower than those of the normal group. Higher contents of Leptin andob-Rwere noted in the 21-day stress group compared with control rats, while NPY expression was not statistically different. Xiaoyaosan powder can significantly downregulate the contents of leptin andob-Rin the hypothalamus of stressed rats. These findings suggest that increase ofob-Rexpression in the ARC is possibly one key central neuroendocrine change for the somatic discomfort. Weight loss and decreased food intake in rats caused by the binding of leptin toob-Rin hypothalamus do not appear to utilize the NPY pathway. This study also suggests thatob-Rin the ARC may act as the target of Xiaoyaosan in regulating the symptoms such as appetite decrease and bodyweight loss under chronic stress.

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