Central overexpression of leptin antagonist reduces wheel running and underscores importance of endogenous leptin receptor activity in energy homeostasis

We used recombinant adeno-associated virus (rAAV)-mediated gene delivery to overexpress a mutant of rat leptin yielding a protein that acts as a neutral leptin receptor antagonist. The long-term consequences of this overexpression on body weight homeostasis and physical activity, as assessed by voluntary wheel running (WR), were determined in F344 × Brown Norway (BN) rats. Leptin antagonist overexpression was confirmed by examination of mRNA levels in the hypothalamus. Food consumption and body weight gain were exacerbated in the antagonist group during both chow and high-fat feeding periods over the 192-day experiment. In a second experiment, a lower dose of antagonist vector was used that resulted in no change in food consumption but still increased body weight. The degree of antagonist overexpression was sufficient to partially block signal transducer and activator of transcription 3 (STAT3) phosphorylation due to administration of an acute submaximal dose of leptin. Rats were provided free access to running wheels for 4 days during both the chow and high-fat feeding periods. With both antagonist doses and during both chow and high-fat feeding, WR was substantially less with antagonist overexpression. In contrast, when leptin was overexpressed in the hypothalamus, WR activity was increased by greater than twofold. At death, adiposity and serum leptin levels were greater in the antagonist group. These data indicate that submaximal central leptin receptor blockade promotes obesity and diminishes WR activity. These findings underscore the critical role of unrestrained leptin receptor activity in long-term energy homeostasis and suggest that even minor disruption of leptin receptor function can promote obesity.

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Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

Molecular and Cellular Biology ◽

10.1128/mcb.00503-14 ◽

2014 ◽

Vol 35 (1) ◽

pp. 26-40 ◽

Cited By ~ 33

Author(s):

Ahmed Lawan ◽

Lei Zhang ◽

Florian Gatzke ◽

Kisuk Min ◽

Michael J. Jurczak ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Kinase ◽

Glucose Metabolism ◽

Energy Homeostasis ◽

Mitogen Activated Protein Kinase ◽

Hepatic Insulin Resistance ◽

Fibroblast Growth Factor 21 ◽

High Fat ◽

Mitogen Activated Protein ◽

Fat Feeding

The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis.

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COMPARISON EFFECT OF CV 12, ST 36 AND ST 40 EA ON SHORT TERM ENERGY BALANCE REGULATION IN HIGH FAT DIET RAT

Folia Medica Indonesiana ◽

10.20473/fmi.v52i3.5448 ◽

2017 ◽

Vol 52 (3) ◽

pp. 174

Author(s):

Purwo Sri Rejeki ◽

Harjanto Harjanto ◽

Raden Argarini ◽

Imam Subadi

Keyword(s):

Body Weight ◽

Blood Glucose ◽

Energy Balance ◽

High Fat Diet ◽

Energy Homeostasis ◽

Continuous Wave ◽

Positive Control ◽

Control Group ◽

High Fat ◽

Short Term

The aim of this study was to determine the comparative effects of EA (EA) on the CV12, ST36 and ST40 to weight gain prevention over the short-term regulation of energy balance. The study was conducted with a completely randomized design. Rats were divided into five groups: negative control group (no treatment, n=5), positive control (sham EA/back, n=5), EA CV 12 (n=6), EA ST 36 (n=6) and EA ST 40 (n=7). Rats were exposed to high-fat diet for two weeks and EA was simultaneously performed once daily, five days a week for two weeks with 2 Hz, for 10 minutes with continuous wave. Body weight, BMI, front limb circumference and rear were measured during study. Levels of blood glucose, cholesterol, triglycerides, LDL and HDL were measured at the end of the study; which reflects the short-term regulation of energy homeostasis. For weight loss, EA CV12, ST36 and ST40 group have lost weight significantly compared to the negative and positive control group. The ST40 group has a significant decrease than ST36 and CV12. The most significant decrease in BMI found in the ST40 group. EA did not affect blood glucose levels, but modulated blood lipid profile. In ST 40 group there was a significant decrease in cholesterol, LDL and triglycerides. EA at point ST 40 is potential in preventing increased body weight and BMI in rats exposed to high-fat diet compared to the CV 12 and ST 36. ST 40 is a point with a potential of lowering LDL and triglycerides serum so that it can play a role in the short term regulation of energy homeostasis but also in the prevention of dyslipidemia.

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Acute (24 h) activation of peroxisome proliferator-activated receptor-alpha (PPARalpha) reverses high-fat feeding-induced insulin hypersecretion in vivo and in perifused pancreatic islets

Journal of Endocrinology ◽

10.1677/joe.0.1770197 ◽

2003 ◽

Vol 177 (2) ◽

pp. 197-205 ◽

Cited By ~ 27

Author(s):

MJ Holness ◽

ND Smith ◽

GK Greenwood ◽

MC Sugden

Keyword(s):

Insulin Secretion ◽

Ex Vivo ◽

Peroxisome Proliferator ◽

High Fat ◽

Intravenous Glucose ◽

Perifused Islets ◽

Glucose Stimulated Insulin Secretion ◽

Fat Feeding

Abnormal depletion or accumulation of islet lipid may be important for the development of pancreatic beta cell failure. Long-term lipid sensing by beta cells may be co-ordinated via peroxisome proliferator-activated receptors (PPARs). We investigated whether PPARalpha activation in vivo for 24 h affects basal and glucose-stimulated insulin secretion in vivo after intravenous glucose administration and ex vivo in isolated perifused islets. Insulin secretion after intravenous glucose challenge was greatly increased by high-fat feeding (4 weeks) but glucose tolerance was minimally perturbed, demonstrating insulin hypersecretion compensated for insulin resistance. The effect of high-fat feeding to enhance glucose-stimulated insulin secretion was retained in perifused islets demonstrating a stable, long-term effect of high-fat feeding to potentiate islet glucose stimulus-secretion coupling. Treatment of high-fat-fed rats with WY14,643 for 24 h reversed insulin hypersecretion in vivo without impairing glucose tolerance, suggesting improved insulin action, and ex vivo in perfused islets. PPARalpha activation only affected hypersecretion of insulin since glucose-stimulated insulin secretion was unaffected by WY14,643 treatment in vivo in control rats or in perifused islets from control rats. Our data demonstrate that activation of PPARalpha for 24 h can oppose insulin hypersecretion elicited by high-fat feeding via stable long-term effects exerted on islet function. PPARalpha could, therefore, participate in ameliorating abnormal glucose homeostasis and hyperinsulinaemia in dietary insulin resistance via modulation of islet function, extending the established requirement for PPARalpha for normal islet lipid homeostasis.

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Quercetin Ameliorates Chronic Type 2 Diabetes Induced by Long-Term High-Fat, High-Sucrose Diet via Modifying Expression of Genes Involved in Energy Homeostasis and Inflammation

Journal of Pharmaceutical Sciences & Emerging Drugs ◽

10.4172/2380-9477.1000117 ◽

2016 ◽

Vol 04 (02) ◽

Author(s):

Almass A Abuzaid ◽

Mohamed A Osman ◽

Abdalla O Elkhawad

Keyword(s):

Type 2 Diabetes ◽

Energy Homeostasis ◽

High Fat ◽

Chronic Type ◽

Expression Of Genes ◽

Sucrose Diet ◽

High Sucrose Diet ◽

High Sucrose

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Changes in Expression of the Genes for the Leptin Signaling in Hypothalamic-Pituitary Selected Areas and Endocrine Responses to Long-Term Manipulation in Body Weight and Resistin in Ewes

International Journal of Molecular Sciences ◽

10.3390/ijms21124238 ◽

2020 ◽

Vol 21 (12) ◽

pp. 4238

Author(s):

Dorota Anna Zieba ◽

Weronika Biernat ◽

Malgorzata Szczesna ◽

Katarzyna Kirsz ◽

Justyna Barć ◽

...

Keyword(s):

Body Weight ◽

Leptin Receptor ◽

Fat Body ◽

Density Lipoprotein ◽

Reproductive Hormones ◽

Leptin Resistance ◽

Nonesterified Fatty Acid ◽

Cytokine Signaling ◽

Leptin Signaling

Both long-term undernutrition and overnutrition disturb metabolic balance, which is mediated partially by the action of two adipokines, leptin and resistin (RSTN). In this study, we manipulated the diet of ewes to produce either a thin (lean) or fat (fat) body condition and investigated how RSTN affects endocrine and metabolic status under different leptin concentrations. Twenty ewes were distributed into four groups (n = 5): the lean and fat groups were administered with saline (Lean and Fat), while the Lean-R (Lean-Resistin treated) and Fat-R (Fat-Resistin treated) groups received recombinant bovine resistin. Plasma was assayed for LH, FSH, PRL, RSTN, leptin, GH, glucose, insulin, total cholesterol, nonesterified fatty acid (NEFA), high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides. Expression levels of a suppressor of cytokine signaling (SOCS-3) and the long form of the leptin receptor (LRb) were determined in selected brain regions, such as the anterior pituitary, hypothalamic arcuate nucleus, preoptic area and ventro- and dorsomedial nuclei. The results indicate long-term alterations in body weight affect RSTN-mediated effects on metabolic and reproductive hormones concentrations and the expression of leptin signaling components: LRb and SOCS-3. This may be an adaptive mechanism to long-term changes in adiposity during the state of long-day leptin resistance.

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Adiponectin is required to mediate rimonabant-induced improvement of insulin sensitivity but not body weight loss in diet-induced obese mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90824.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. R929-R935 ◽

Cited By ~ 29

Author(s):

Stéphanie Migrenne ◽

Amélie Lacombe ◽

Anne-Laure Lefèvre ◽

Marie-Pierre Pruniaux ◽

Etienne Guillot ◽

...

Keyword(s):

Body Weight ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Energy Homeostasis ◽

Hepatic Glucose Production ◽

Body Weight Loss ◽

Metabolic Effects ◽

Wild Type ◽

High Fat ◽

Wild Type Littermate

The increase in adiponectin levels in obese patients with untreated dyslipidemia and its mRNA expression in adipose tissue of obese animals are one of the most interesting consequences of rimonabant treatment. Thus, part of rimonabant's metabolic effects could be related to an enhancement of adiponectin secretion and its consequence on the modulation of insulin action, as well as energy homeostasis. The present study investigated the effects of rimonabant in adiponectin knockout mice (Ad−/−) exposed to diet-induced obesity conditions. Six-week-old Ad−/− male mice and their wild-type littermate controls (Ad+/+) were fed a high-fat diet for 7 mo. During the last month, animals were administered daily either with vehicle or rimonabant by mouth (10 mg/kg). High-fat feeding induced weight gain by about 130% in both wild-type and Ad−/− mice. Obesity was associated with hyperinsulinemia and insulin resistance. Treatment with rimonabant led to a significant and similar decrease in body weight in both Ad+/+ and Ad−/− mice compared with vehicle-treated animals. In addition, rimonabant significantly improved insulin sensitivity in Ad+/+ mice compared with Ad+/+ vehicle-treated mice by decreasing hepatic glucose production and increasing glucose utilization index in both visceral and subcutaneous adipose tissue. In contrast, rimonabant failed to improve insulin sensitivity in Ad−/− mice, despite the loss in body weight. Rimonabant's effect on body weight appeared independent of the adiponectin pathway, whereas adiponectin seems required to mediate rimonabant-induced improvement of insulin sensitivity in rodents.

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Adult offspring of high-fat diet-fed dams can have normal glucose tolerance and body composition

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174414000154 ◽

2014 ◽

Vol 5 (3) ◽

pp. 229-239 ◽

Cited By ~ 10

Author(s):

K. M. Platt ◽

R. J. Charnigo ◽

K. J. Pearson

Keyword(s):

Body Composition ◽

Body Weight ◽

Glucose Tolerance ◽

Impaired Glucose Tolerance ◽

High Fat Diet ◽

High Fat ◽

High Fat Diets ◽

Normal Glucose ◽

Fat Diets

Maternal high-fat diet consumption and obesity have been shown to program long-term obesity and lead to impaired glucose tolerance in offspring. Many rodent studies, however, use non-purified, cereal-based diets as the control for purified high-fat diets. In this study, primiparous ICR mice were fed purified control diet (10–11 kcal% from fat of lard or butter origin) and lard (45 or 60 kcal% fat) or butter (32 or 60 kcal% fat)-based high-fat diets for 4 weeks before mating, throughout pregnancy, and for 2 weeks of nursing. Before mating, female mice fed the 32 and 60% butter-based high-fat diets exhibited impaired glucose tolerance but those females fed the lard-based diets showed normal glucose disposal following a glucose challenge. High-fat diet consumption by female mice of all groups decreased lean to fat mass ratios during the 4th week of diet treatment compared with those mice consuming the 10–11% fat diets. All females were bred to male mice and pregnancy and offspring outcomes were monitored. The body weight of pups born to 45% lard-fed dams was significantly increased before weaning, but only female offspring born to 32% butter-fed dams exhibited long-term body weight increases. Offspring glucose tolerance and body composition were measured for at least 1 year. Minimal, if any, differences were observed in the offspring parameters. These results suggest that many variables should be considered when designing future high-fat diet feeding and maternal obesity studies in mice.

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