Mechanisms of Amylin/Leptin Synergy in Rodent Models

Endocrinology ◽  
2010 ◽  
Vol 151 (1) ◽  
pp. 143-152 ◽  
Author(s):  
Victoria F. Turek ◽  
James L. Trevaskis ◽  
Barry E. Levin ◽  
Ambrose A. Dunn-Meynell ◽  
Boman Irani ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Leptin Receptor ◽  
Therapeutic Potential ◽  
Ventromedial Hypothalamus ◽  
Signal Transducer ◽  
Leptin Signaling ◽  
Reduced Body ◽  
Epididymal Fat ◽  
Transcription 3

Abstract The present studies aimed to identify mechanisms contributing to amylin/leptin synergy in reducing body weight and adiposity. We reasoned that if amylin/leptin harnessed complementary neuronal pathways, then in the leptin-sensitive state, amylin should augment leptin signaling/binding and that in the absence of endogenous amylin, leptin signaling should be diminished. Amylin (50 μg/kg, ip) amplified low-dose leptin-stimulated (15 μg/kg, ip) phosphorylated signal transducer and activator of transcription-3 signaling within the arcuate nucleus (ARC) in lean rats. Amylin (50 μg/kg · d) or leptin (125 μg/kg · d) infusion to lean rats decreased 28-d food intake (14 and 10%, respectively), body weight (amylin by 4.3%, leptin by 4.9%), and epididymal fat (amylin by 19%, leptin by 37%). Amylin/leptin co-infusion additively decreased food intake (by 26%) and reduced body weight (by 15%) and epididymal fat (by 78%; all P < 0.05 vs. all groups) in a greater than mathematically additive manner, consistent with synergy. Amylin increased leptin binding within the ventromedial hypothalamus (VMN) by 35% and dorsomedial hypothalamus by 47% (both P < 0.05 vs. vehicle). Amylin/leptin similarly increased leptin binding in the VMN by 40% and ARC by 70% (P < 0.05 vs. vehicle). In amylin-deficient mice, hypothalamic leptin receptor mRNA expression was reduced by 50%, leptin-stimulated phosphorylated signal transducer and activator of transcription-3 within ARC and VMN was reduced by 40%, and responsiveness to leptin’s (1 mg/kg · d for 28 d) weight-reducing effects was attenuated (all P < 0.05 vs. wild-type controls). We suggest that amylin/leptin’s marked weight- and fat-reducing effects are due to activation of intrinsic synergistic neuronal signaling pathways and further point to the integrated neurohormonal therapeutic potential of amylin/leptin agonism in obesity.

scholarly journals Increased Hypothalamic Signal Transducer and Activator of Transcription 3 Phosphorylation after Hindbrain Leptin Injection

Endocrinology ◽  
2010 ◽  
Vol 151 (4) ◽  
pp. 1509-1519 ◽  
Author(s):  
Marieke Ruiter ◽  
Patricia Duffy ◽  
Steven Simasko ◽  
Robert C. Ritter
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Fourth Ventricle ◽  
Leptin Receptor ◽  
Janus Kinase ◽  
Signal Transducer ◽  
Solitary Tract ◽  
Stat3 Signaling ◽  
Stat3 Phosphorylation ◽  
Transcription 3

Reduction of food intake and body weight by leptin is attributed largely to its action in the hypothalamus. However, the signaling splice variant of the leptin receptor, LRb, also is expressed in the hindbrain, and leptin injections into the fourth cerebral ventricle or dorsal vagal complex are associated with reductions of feeding and body weight comparable to those induced by forebrain leptin administration. Although these observations suggest direct hindbrain action of leptin on feeding and body weight, the possibility that hindbrain leptin administration also activates the Janus kinase/signal transducer and activator of transcription 3 (STAT3) signaling in the hypothalamus has not been investigated. Confirming earlier work, we found that leptin produced comparable reductions of feeding and body weight when injected into the lateral ventricle or the fourth ventricle. We also found that lateral and fourth ventricle leptin injections produced comparable increases of STAT3 phosphorylation in both the hindbrain and the hypothalamus. Moreover, injection of 50 ng of leptin directly into the nucleus of the solitary tract also increased STAT3 phosphorylation in the hypothalamic arcuate and ventromedial nuclei. Increased hypothalamic STAT3 phosphorylation was not due to elevation of blood leptin concentrations and the pattern of STAT3 phosphorylation did not overlap distribution of the retrograde tracer, fluorogold, injected via the same cannula. Our observations indicate that even small leptin doses administered to the hindbrain can trigger leptin-related signaling in the forebrain, and raise the possibility that STAT3 phosphorylation in the hypothalamus may contribute to behavioral and metabolic changes observed after hindbrain leptin injections.

scholarly journals Electroacupuncture Reduces Weight Gain Induced by Rosiglitazone through PPARγand Leptin Receptor in CNS

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Xinyue Jing ◽  
Chen Ou ◽  
Hui Chen ◽  
Tianlin Wang ◽  
Bin Xu ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Food Intake ◽  
Leptin Receptor ◽  
The Body ◽  
Signal Transducer ◽  
Antidiabetic Effect ◽  
Lipid Contents ◽  
Transcription 3

We investigate the effect of electroacupuncture (EA) on protecting the weight gain side effect of rosiglitazone (RSG) in type 2 diabetes mellitus (T2DM) rats and its possible mechanism in central nervous system (CNS). Our study showed that RSG (5 mg/kg) significantly increased the body weight and food intake of the T2DM rats. After six-week treatment with RSG combined with EA, body weight, food intake, and the ratio of IWAT to body weight decreased significantly, whereas the ratio of BAT to body weight increased markedly. HE staining indicated that the T2DM-RSG rats had increased size of adipocytes in their IWAT, but EA treatment reduced the size of adipocytes. EA effectively reduced the lipid contents without affecting the antidiabetic effect of RSG. Furthermore, we noticed that the expression of PPARγgene in hypothalamus was reduced by EA, while the expressions of leptin receptor and signal transducer and activator of transcription 3 (STAT3) were increased. Our results suggest that EA is an effective approach for inhibiting weight gain in T2DM rats treated by RSG. The possible mechanism might be through increased levels of leptin receptor and STAT3 and decreased PPARγexpression, by which food intake of the rats was reduced and RSG-induced weight gain was inhibited.

scholarly journals Chronic Stimulation of Leptin on Food Intake and Body Weight after Microinjection into the Ventromedial Hypothalamus of Conscious Rats

1970 ◽  
Vol 19 (2) ◽  
pp. 70-75
Author(s):  
Md Shahidul Haque ◽  
Takashi Shimazu
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Low Dose ◽  
Ventromedial Hypothalamus ◽  
Chronic Stimulation ◽  
Dramatic Effect ◽  
Reduced Body ◽  
Medial Hypothalamus ◽  
Control Body ◽  
Stimulation Of

A very low dose of leptin (50 ng) was microinjected into the ventro-medial hypothalamus (VMH) of each rat daily once for three days. Food intake and body weight were measured after leptin injections. Microinjection of leptin into the VMH reduced food intake by 33.3 % significantly (P<0.01) during three days of leptin injection compared to the control. Body weight was measured after 24 h, 48 h and 72 h of leptin injection. After 24 h (P<0.01) and 48 h (P<0.05) of leptin injection, body weight was reduced significantly compared to that of rat before injection. Similarly, after 72 h of leptin injection, a significant reduced body weight was observed (P<0.1). A significant (P<0.001) reduced changes of body weight were found after 24 h, 48 h and 72 h after injection into the VMH when compared to the respective controls injected with saline. The results suggest that leptin has dramatic effect on reducing body weight by inhibition of food intake.   doi: 10.3329/taj.v19i2.3154 TAJ 2006; 19(2): 70-75

scholarly journals Arcuate Nucleus-Specific Leptin Receptor Gene Therapy Attenuates the Obesity Phenotype of Koletsky (fak/fak) Rats

Endocrinology ◽  
2003 ◽  
Vol 144 (5) ◽  
pp. 2016-2024 ◽  
Author(s):  
Gregory J. Morton ◽  
Kevin D. Niswender ◽  
Christopher J. Rhodes ◽  
Martin G. Myers ◽  
James E. Blevins ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Body Weight ◽  
Food Intake ◽  
Energy Homeostasis ◽  
Arcuate Nucleus ◽  
Leptin Receptor ◽  
Receptor Expression ◽  
Wild Type ◽  
Leptin Signaling ◽  
Adenoviral Gene Therapy

Leptin signaling in the hypothalamic arcuate nucleus (ARC) is hypothesized to play an important role in energy homeostasis. To investigate whether leptin signaling limited to this brain area is sufficient to reduce food intake and body weight, we used adenoviral gene therapy to express the signaling isoform of the leptin receptor, leprb, in the ARC of leptin receptor-deficient Koletsky (fak/fak) rats. Successful expression of adenovirus containing leprb (Ad-leprb) selectively in the ARC was documented by in situ hybridization. Using real-time PCR, we further demonstrated that bilateral microinjection of Ad-leprb into the ARC restored low hypothalamic levels of leprb mRNA to values approximating those of wild-type (Fak/Fak) controls. Restored leptin receptor expression in the ARC reduced both mean daily food intake (by 13%) and body weight gain (by 33%) and increased hypothalamic proopiomelanocortin mRNA by 65% while decreasing neuropeptide Y mRNA levels by 30%, relative to fak/fak rats injected with a control adenovirus (Ad-lacZ) (P &lt; 0.05 for each comparison). In contrast, Ad-leprb delivery to either the lateral hypothalamic area of fak/fak rats or to the ARC of wild-type Fak/Fak rats had no effect on any of these parameters. These findings collectively support the hypothesis that leptin receptor signaling in the ARC is sufficient to mediate major effects of leptin on long-term energy homeostasis. Adenoviral gene therapy is thus a viable strategy with which to study the physiological importance of specific molecules acting in discrete brain areas.

scholarly journals Large Litter Rearing Improves Leptin Sensitivity and Hypothalamic Appetite Markers in Offspring of Rat Dams Fed High-Fat Diet During Pregnancy and Lactation

Endocrinology ◽  
2014 ◽  
Vol 155 (9) ◽  
pp. 3421-3433 ◽  
Author(s):  
Bo Sun ◽  
Lin Song ◽  
Kellie L. K. Tamashiro ◽  
Timothy H. Moran ◽  
Jianqun Yan
Keyword(s):  
Body Weight ◽  
Glucose Tolerance ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
High Fat ◽  
Suppressor Of Cytokine Signaling ◽  
Male And Female ◽  
Leptin Signaling ◽  
Large Litter ◽  
Transcription 3

Abstract Maternal high-fat (HF) diet has long-term consequences on the offspring's metabolic phenotype. Here, we determined the effects of large litter (LL) rearing in offspring of rat dams fed HF diet during gestation and lactation. Pregnant Sprague-Dawley rats were maintained on standard chow (CHOW) or HF diet throughout gestation and lactation. Pups were raised in normal litters (NLs) (10 pups/dam) or LLs (16 pups/dam) during lactation, resulting in 4 groups: CHOW-NL, CHOW-LL, HF-NL, and HF-LL. The offspring were weaned onto to either CHOW or HF diet on postnatal day 21. Male and female pups with maternal HF diet (HF-NL) had greater body weight and adiposity, higher plasma leptin levels, impaired glucose tolerance, abnormal hypothalamic leptin signaling pathways (lower leptin receptor-b [OB-Rb] and signal transducer and activator of transcription 3, higher suppressor of cytokine signaling 3 mRNA expression) and appetite markers (lower neuropeptide Y and Agouti-related peptide mRNA expression), and reduced phospho-signal transducer and activator of transcription 3 level in response to leptin in the arcuate nucleus at weaning, whereas LL rearing normalized these differences. When weaned onto CHOW diet, adult male offspring from HF diet-fed dams continued to have greater adiposity, higher leptin levels, and lower hypothalamic OB-Rb, and LL rearing improved them. When weaned onto HF diet, both adult male and female offspring with maternal HF diet had greater body weight and adiposity, higher leptin levels, impaired glucose tolerance, lower OB-Rb, and higher suppressor of cytokine signaling 3 in hypothalamus compared with those of CHOW dams, whereas LL rearing improved most of them except male OB-Rb expression. Our data suggest that LL rearing improves hypothalamic leptin signaling pathways and appetite markers in an age- and sex-specific manner in this model.

scholarly journals Deficiency of PTP1B in Leptin Receptor-Expressing Neurons Leads to Decreased Body Weight and Adiposity in Mice

Endocrinology ◽  
2012 ◽  
Vol 153 (9) ◽  
pp. 4227-4237 ◽  
Author(s):  
Ryan C. Tsou ◽  
Derek J. Zimmer ◽  
Bart C. De Jonghe ◽  
Kendra K. Bence
Keyword(s):  
Body Weight ◽  
Leptin Receptor ◽  
Body Weight Gain ◽  
Tyrosine Phosphatase ◽  
Negative Regulator ◽  
Metabolic Effects ◽  
Metabolic Phenotype ◽  
Leptin Signaling ◽  
Reduced Body ◽  
Leptin Sensitivity

Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed tyrosine phosphatase implicated in the negative regulation of leptin and insulin receptor signaling. PTP1B−/− mice possess a lean metabolic phenotype attributed at least partially to improved hypothalamic leptin sensitivity. Interestingly, mice lacking both leptin and PTP1B (ob/ob:PTP1B−/−) have reduced body weight compared with mice lacking leptin only, suggesting that PTP1B may have important leptin-independent metabolic effects. We generated mice with PTP1B deficiency specifically in leptin receptor (LepRb)-expressing neurons (LepRb-PTP1B−/−) and compared them with LepRb-Cre-only wild-type (WT) controls and global PTP1B−/− mice. Consistent with PTP1B's role as a negative regulator of leptin signaling, our results show that LepRb-PTP1B−/− mice are leptin hypersensitive and have significantly reduced body weight when maintained on chow or high-fat diet (HFD) compared with WT controls. LepRb-PTP1B−/− mice have a significant decrease in adiposity on HFD compared with controls. Notably, the extent of attenuated body weight gain on HFD, as well as the extent of leptin hypersensitivity, is similar between LepRb-PTP1B−/− mice and global PTP1B−/− mice. Overall, these results demonstrate that PTP1B deficiency in LepRb-expressing neurons results in reduced body weight and adiposity compared with WT controls and likely underlies the improved metabolic phenotype of global and brain-specific PTP1B-deficient models. Subtle phenotypic differences between LepRb-PTP1B−/− and global PTP1B−/− mice, however, suggest that PTP1B independent of leptin signaling may also contribute to energy balance in mice.

scholarly journals Effects of Acute Changes in Neonatal Leptin Levels on Food Intake and Long-Term Metabolic Profiles in Rats

Endocrinology ◽  
2011 ◽  
Vol 152 (11) ◽  
pp. 4116-4126 ◽  
Author(s):  
Miriam Granado ◽  
Cristina García-Cáceres ◽  
Esther Fuente-Martín ◽  
Francisca Díaz ◽  
Virginia Mela ◽  
...  
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Leptin Receptor ◽  
Uncoupling Protein ◽  
Metabolic Effects ◽  
Metabolic Profiles ◽  
Mrna Levels ◽  
Reduced Body ◽  
Acute Changes

In rodents there is a rise in serum leptin levels between postnatal days (PND) 5 and 14, with this neonatal leptin surge reported to modulate the maturation of hypothalamic circuits involved in appetite regulation. We hypothesized that acute changes in neonatal leptin levels have different long-term metabolic effects depending on how and when this surge is modified. To advance the timing of the normal leptin peak, male Wistar rats were injected with leptin (sc, 3 μg/g) on PND 2. To ablate the leptin peak on PND 10, a pegylated leptin antagonist (sc, 9 μg/g) was injected. Controls received vehicle. All rats were allowed to eat ad libitum until PND 150. Increased leptin on PND 2 reduced food intake (P &lt; 0.01) after 3 months of age with no effect on body weight. Levels of total ghrelin were reduced (P &lt; 0.001) and acylated ghrelin increased (P &lt; 0.05), with no other modifications in metabolic hormones. In contrast, treatment with the leptin antagonist on PND 9 did not affect food intake but reduced body weight beginning around PND 60 (P &lt; 0.02). This was associated with a reduction in fat mass, insulin (P &lt; 0.01), and leptin (P &lt; 0.007) levels and an increase in testosterone levels (P &lt; 0.01). Hypothalamic neuropeptide Y (P &lt; 0.05) and leptin receptor (P &lt; 0.005) mRNA levels were reduced, whereas mRNA levels for uncoupling protein 2 (P &lt; 0.005) were increased in visceral fat, which may indicate an increase in energy expenditure. In conclusion, acute changes in neonatal leptin levels induce different metabolic profiles depending on how and when leptin levels are modified.

Metabolic responses to leptin in obese db/db mice are strain dependent

2001 ◽  
Vol 281 (1) ◽  
pp. R115-R132 ◽  
Author(s):  
Ruth B. S. Harris ◽  
Tiffany D. Mitchell ◽  
Xiaolang Yan ◽  
Jacob S. Simpson ◽  
Stephen M. Redmann
Keyword(s):  
Body Weight ◽  
Food Intake ◽  
Body Fat ◽  
Leptin Receptor ◽  
Short Form ◽  
Fasting Blood Glucose ◽  
Male Mice ◽  
Background Strain ◽  
Reduced Body ◽  
Intraperitoneal Infusion

Obese, diabetic C57BL/Ks db/db mice that lack the long-form leptin receptor exhibit no decrease in body weight or food intake when treated with leptin. Here we compared responses to leptin in two strains of db/db mice: C57BL/6J mice that are hyperglycemic and hyperinsulinemic and C57BL/Ks that are hyperglycemic and normo- or hypoinsulinemic. Chronic intraperitoneal infusion of 10 μg leptin/day partially reversed hyperglycemia in C57BL/6J male mice but exaggerated the diabetic state of female mice. Bolus intraperitoneal injections of 40 μg leptin/day did not effect glucose in either strain of male db/db mice, whereas chronic intraperitoneal infusion of 20 μg leptin/day significantly reduced fasting blood glucose in male mice from both strains, especially C57BL/6J mice. Food intake, body weight, rectal temperature, and body fat did not change. Chronic intraperitoneal infusion of 10 μg leptin/day significantly reduced body fat in lean db/+ C57BL/6J but not in C57BL/Ks mice. Thus peripherally administered leptin is active in mice that have only short-form leptin receptors, and the response is dependent on the method of leptin administration and the background strain.

scholarly journals High Intakes of [6S]-5-Methyltetrahydrofolic Acid Compared with Folic Acid during Pregnancy Programs Central and Peripheral Mechanisms Favouring Increased Food Intake and Body Weight of Mature Female Offspring

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1477
Author(s):  
Emanuela Pannia ◽  
Rola Hammoud ◽  
Ruslan Kubant ◽  
Jong Yup Sa ◽  
Rebecca Simonian ◽  
...  
Keyword(s):  
Body Weight ◽  
Folic Acid ◽  
Food Intake ◽  
Leptin Receptor ◽  
Liver Weight ◽  
Female Offspring ◽  
Mature Female ◽  
Cytokine Signaling ◽  
Light Cycle ◽  
Energy Regulation

Supplementation with [6S]-5-methyltetrahydrofolic acid (MTHF) is recommended as an alternative to folic acid (FA) in prenatal supplements. This study compared equimolar gestational FA and MTHF diets on energy regulation of female offspring. Wistar rats were fed an AIN-93G diet with recommended (2 mg/kg diet) or 5-fold (5X) intakes of MTHF or FA. At weaning, female offspring were fed a 45% fat diet until 19 weeks. The 5X-MTHF offspring had higher body weight (>15%), food intake (8%), light-cycle energy expenditure, and lower activity compared to 5X-FA offspring (p < 0.05). Both the 5X offspring had higher plasma levels of the anorectic hormone leptin at birth (60%) and at 19 weeks (40%), and lower liver weight and total liver lipids compared to the 1X offspring (p < 0.05). Hypothalamic mRNA expression of leptin receptor (ObRb) was lower, and of suppressor of cytokine signaling-3 (Socs3) was higher in the 5X-MTHF offspring (p < 0.05), suggesting central leptin dysregulation. In contrast, the 5X-FA offspring had higher expression of genes encoding for dopamine and GABA- neurotransmitter receptors (p < 0.01), consistent with their phenotype and reduced food intake. When fed folate diets at the requirement level, no differences were found due to form in the offspring. We conclude that MTHF compared to FA consumed at high levels in the gestational diets program central and peripheral mechanisms to favour increased weight gain in the offspring. These pre-clinical findings caution against high gestational intakes of folates of either form and encourage clinical trials examining their long-term health effects when consumed during pregnancy.

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