Role of neonatal hyperleptinaemia on serum adiponectin and suppressor of cytokine signalling-3 expression in young rats

Previously we had shown that neonatal leptin treatment programmes for both hyperleptinaemia and hyperinsulinaemia, which lead to leptin resistance and low expression of the hypothalamic leptin receptor (OB-Rb) of rats aged 150 d. Here we investigated in young post-weaned rats (age 30 d) if leptin treatment during lactation induces leptin and insulin resistance and if those changes are accompanied by changes in the suppressor of cytokine signalling-3 (SOCS-3) expression and serum adiponectin concentration. After delivery, the pups were divided into two groups: (1) a leptin group (Lep) that were injected with leptin daily (8 μg/100 g body weight subcutaneously) for the first 10 d of lactation; (2) a control (C) group, receiving saline. After weaning (day 21), body weight was monitored until the animals were age 30 d. They were tested for food intake in response to either leptin (0·5 mg/kg body weight intraperitoneally) (CL, LepL) or saline (CSal, LepSal) when they were aged 30 d. The CL group showed lower food intake, but no response was observed in the LepL group, suggesting leptin resistance. The Lep group had hyperleptinaemia (five-fold), hyperinsulinaemia (+42·5 %) and lower levels of serum adiponectin ( − 43·2 %). The hypothalamic expression of OB-Rb was lower ( − 22 %) and SOCS-3 was higher (+52·8 %) in the Lep group. We conclude that neonatal leptin treatment programmes for leptin resistance as soon as 30 d and suggests that SOCS-3 appears to be of particular importance in this event. In the Lep group, the lower serum adiponectin levels were accompanied by higher serum insulin, indicating a probable insulin resistance.

Download Full-text

Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications

International Journal of Molecular Sciences ◽

10.3390/ijms20092109 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2109 ◽

Cited By ~ 6

Author(s):

Arulkumar Nagappan ◽

Jooyeon Shin ◽

Myeong Ho Jung

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Insulin Sensitivity ◽

Hepatic Steatosis ◽

Cannabinoid Receptor ◽

Inflammatory Responses ◽

Hepatic Insulin Resistance ◽

Leptin Resistance ◽

Peripheral Tissues

Endogenous cannabinoids (ECs) are lipid-signaling molecules that specifically bind to cannabinoid receptor types 1 and 2 (CB1R and CB2R) and are highly expressed in central and many peripheral tissues under pathological conditions. Activation of hepatic CB1R is associated with obesity, insulin resistance, and impaired metabolic function, owing to increased energy intake and storage, impaired glucose and lipid metabolism, and enhanced oxidative stress and inflammatory responses. Additionally, blocking peripheral CB1R improves insulin sensitivity and glucose metabolism and also reduces hepatic steatosis and body weight in obese mice. Thus, targeting EC receptors, especially CB1R, may provide a potential therapeutic strategy against obesity and insulin resistance. There are many CB1R antagonists, including inverse agonists and natural compounds that target CB1R and can reduce body weight, adiposity, and hepatic steatosis, and those that improve insulin sensitivity and reverse leptin resistance. Recently, the use of CB1R antagonists was suspended due to adverse central effects, and this caused a major setback in the development of CB1R antagonists. Recent studies, however, have focused on development of antagonists lacking adverse effects. In this review, we detail the important role of CB1R in hepatic insulin resistance and the possible underlying mechanisms, and the therapeutic potential of CB1R targeting is also discussed.

Download Full-text

Adiponectin, an Adipocyte-Derived Protein, Predicts Future Insulin Resistance: Two-Year Follow-Up Study in Japanese Population

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2003-031163 ◽

2004 ◽

Vol 89 (1) ◽

pp. 87-90 ◽

Cited By ~ 149

Author(s):

Yukihiro Yamamoto ◽

Hiroshi Hirose ◽

Ikuo Saito ◽

Kanako Nishikai ◽

Takao Saruta

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Lipid Profile ◽

Adiponectin Level ◽

Serum Insulin ◽

Resistance Index ◽

Serum Adiponectin ◽

Model Assessment ◽

Homeostasis Model Assessment ◽

Insulin Resistance Index

It has been reported that the serum adiponectin level was negatively correlated with body mass index (BMI), insulin resistance index, and triglycerides and was positively correlated with high-density lipoprotein cholesterol in several cross-sectional studies. However, the causal relationship has not been elucidated. We investigated whether the baseline adiponectin level could predict subsequent changes in insulin resistance, lipid profile, or body weight in a 2-yr longitudinal study. This study included 590 male Japanese subjects, aged 30–65 yr, who received annual health checkups in both 2000 and 2002. Blood pressure, heart rate, and anthropometric and metabolic parameters, including serum insulin and adiponectin levels, were determined. The insulin resistance index was calculated based on homeostasis model assessment. Baseline adiponectin level was not correlated with the subsequent change in lipid profile or BMI in 2 yr after adjustment for each baseline value. However, the baseline adiponectin level was negatively correlated with subsequent changes in insulin and insulin resistance index based on homeostasis model assessment, even after adjustment for change in BMI (r = −0.162 and r = −0.140, respectively). These findings suggest that the serum adiponectin concentration predicts subsequent changes in insulin resistance, but not in lipid profile or body weight.

Download Full-text

Type 2 diabetes mellitus is associated with lower serum adiponectin level in Bangladeshi population

Mediscope ◽

10.3329/mediscope.v2i2.25405 ◽

2015 ◽

Vol 2 (2) ◽

pp. 16-21

Author(s):

SN Eva ◽

GM Mollah ◽

DK Sunyal ◽

R Zinnat

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Adiponectin Level ◽

Serum Insulin ◽

Serum Adiponectin ◽

Serum Adiponectin Level ◽

Lower Serum ◽

Control Subjects ◽

Bangladeshi Population

The aim of the observational case control study was to find out the association of type 2 diabetes mellitus (T2DM) with serum adiponectin level in Bangladeshi population. This was conducted in the Biomedical Research Group, Research Division, Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM), Dhaka, Bangladesh. Sixty six T2DM subjects and seventy four healthy control subjects were included. Diabetes was diagnosed and classified as per World Health Organization criteria. Serum adiponectin was measured by Enzyme Linked Immunosorbent Assay (ELISA) method. Serum glucose was measured by glucose-oxidase method; serum insulin was measured by chemiluminescence- based ELISA technique. The insulin secretory capacity (HOMA%B), insulin sensitivity (HOMA%S) & insulin resistance (HOMA-IR) were assayed by homeostasis model assessment method. Statistical analysis was performed using SPSS Windows version 11.5. The median (range) fasting serum insulin of control and T2DM subjects were 14.7 (1.9-45.9) and 18.1 (4.1-42.8), respectively. The median (range) serum adiponectin (?g/ml) of the control and T2DM subjects were 8.7 (0.8-16.0) and 6.2 (1.1-22.4). The serum adiponectin of T2DM was significantly lower than the control subjects (p < 0.001). The median (range) HOMA%B values of control and T2DM subjects were 160.1 (33.4-493.4) and 100.5 (17.7-349.3), respectively. The median HOMA%B of T2DM subjects was significantly lower than the control subjects (p < 0.001). The median (range) HOMA%S values of control and T2DM subjects were 44.2 (9.8-339.4) and 32.8 (14.3-154.7), respectively. The median HOMA%S of T2DM group was significantly lower than the control subjects (p < 0.05). The median (range) HOMA-IR of control and T2DM subjects were 3.5 (0.5-11.4) and 5.8 (1.0-28.3), respectively. The median HOMA-IR of T2DM subjects was significantly higher than the control subjects (p < 0.001). The results of the study suggest that T2DM subjects have both insulin secretory defects, insulin resistance and associated with lower serum adiponectin level in Bangladeshi population.Mediscope Vol. 2, No. 2: July 2015, Pages 16-21

Download Full-text

Protein tyrosine phosphatase-1B contributes to LPS-induced leptin resistance in male rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00094.2014 ◽

2015 ◽

Vol 308 (1) ◽

pp. E40-E50 ◽

Cited By ~ 9

Author(s):

Beatriz de Carvalho Borges ◽

Rodrigo C. Rorato ◽

Ernane Torres Uchoa ◽

Paula B. Marangon ◽

Carol F. Elias ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Leptin Receptor ◽

Tyrosine Phosphatase ◽

Body Weight Loss ◽

Male Rats ◽

Leptin Resistance ◽

Reduce Food Intake ◽

Low Grade ◽

Lps Treatment

Leptin resistance is induced by the feedback inhibitors tyrosine phosphatase-1B (PTP1B) and decreased Src homology 2 domain-containing tyrosine phosphatase-2 (SHP-2) signaling. To investigate the participation of PTP1B and SHP-2 in LPS-induced leptin resistance, we injected repeated (6-LPS) intraperitoneal LPS doses (100 μg/kg ip) for comparison with a single (1-LPS) treatment and evaluated the expression of SHP-2, PTP1B, p-ERK1/2, and p-STAT3 in the hypothalamus of male Wistar rats. The single LPS treatment increased the expression of p-STAT3 and PTP1B but not SHP-2. The repeated LPS treatment reduced SHP-2, increased PTP1B, and did not change p-STAT3. We observed that the PTP1B expression induced by the endotoxin was highly colocalized with leptin receptor cells in the hypothalamus of LepRb-IRES-Cre-tdTomato reporter mice. The single, but not the repeated, LPS treatment decreased the food intake and body weight. Leptin had no stimulatory effect on the hypophagia, body weight loss, or pSTAT3 expression in 6-LPS rats, indicating leptin unresponsiveness. Notably, the PTP1B inhibitor (3.0 nmol/rat in 5 μl icv) restored the LPS-induced hypophagia in 6-LPS rats and restored the ability of leptin to reduce food intake and body weight as well as to phosphorylate STAT3 in the arcuate, paraventricular, and ventromedial nuclei of the hypothalamus. The present data suggest that an increased PTP1B expression in the hypothalamus underlies the development of leptin resistance during repeated exposure to LPS. Our findings contribute to understanding the mechanisms involved in leptin resistance during low-grade inflammation as seen in obesity.

Download Full-text

Role of GABA Release From Leptin Receptor-Expressing Neurons in Body Weight Regulation

Endocrinology ◽

10.1210/en.2011-2071 ◽

2012 ◽

Vol 153 (5) ◽

pp. 2223-2233 ◽

Cited By ~ 36

Author(s):

Yuanzhong Xu ◽

William G. O'Brien ◽

Cheng-Chi Lee ◽

Martin G. Myers ◽

Qingchun Tong

Keyword(s):

Body Weight ◽

Food Intake ◽

Leptin Receptor ◽

Gaba Release ◽

Neuron Activity ◽

Chow Diet ◽

Weight Regulation ◽

Body Weight Regulation ◽

The Brain

It is well established that leptin regulates energy balance largely through isoform B leptin receptor-expressing neurons (LepR neurons) in the brain and that leptin activates one subset of LepR neurons (leptin-excited neurons) while inhibiting the other (leptin-inhibited neurons). However, the neurotransmitters released from LepR neurons that mediate leptin action in the brain are not well understood. Previous results demonstrate that leptin mainly acts on γ-aminobutyric acid (GABA)ergic neurons to reduce body weight, and that leptin activates proopiomelanocortin neuron activity by reducing GABA release onto these neurons, suggesting a body weight-promoting role for GABA released from leptin-inhibited neurons. To directly examine the role of GABA release from LepR neurons in body weight regulation, mice with disruption of GABA release specifically from LepR neurons were generated by deletion of vesicular GABA transporter in LepR neurons. Interestingly, these mice developed mild obesity on chow diet and were sensitive to diet-induced obesity, which were associated with higher food intake and lower energy expenditure. Moreover, these mice showed blunted responses in both food intake and body weight to acute leptin administration. These results demonstrate that GABA plays an important role in mediating leptin action. In combination with the previous studies that leptin reduces GABA release onto proopiomelanocortin neurons through leptin-inhibited neurons and that disruption of GABA release from agouti gene-related protein neurons, one subset of LepR-inhibited neurons, leads to a lean phenotype, our results suggest that, under our experimental conditions, GABA release from leptin-excited neuron dominates over leptin-inhibited ones.

Download Full-text

Leptin resistance: unsolved diagnostic issues

Problems of Endocrinology ◽

10.14341/probl201864162-66 ◽

2018 ◽

Vol 64 (1) ◽

pp. 62-66

Author(s):

Daria A. Borodkina ◽

Olga V. Gruzdeva ◽

Olga E. Akbasheva ◽

Ekaterina V. Belik ◽

Elena I. Palicheva ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Skeletal Muscles ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Leptin Resistance ◽

Fatty Tissue ◽

Leptin Receptors ◽

Secretion Regulation ◽

Tissue Sensitivity

Leptin and its receptors are key regulators of body weight and energy homeostasis. A decrease in tissue sensitivity to leptin leads to the development of obesity, insulin resistance, dyslipidemia, etc. Currently, the phenomenon of leptin resistance is explained by a number of mechanisms, including impairment of gene structure, leptin transport through the blood-brain barrier, and leptin receptor signaling. However, it is not known, a decrease in the number of receptors of which area leads to the development of leptin resistance. No relationship has been found between the basal leptin level in obesity and expression of leptin receptors in the skeletal muscles. It is also important to investigate the contribution of fatty tissue of different localization to leptin secretion regulation and activity of its receptors. The term «leptin resistence» reflects a complex pathophysiological phenomenon with broad perspectives for study. In this review, we analyze methods of diagnosing leptin resistance.

Download Full-text

Leptin Receptor Expressing Neurons in the Substantia Nigra Regulate Locomotion, and in The Ventral Tegmental Area Motivation and Feeding

Frontiers in Endocrinology ◽

10.3389/fendo.2021.680494 ◽

2021 ◽

Vol 12 ◽

Author(s):

Véronne A. J. de Vrind ◽

Lisanne J. van ‘t Sant ◽

Annemieke Rozeboom ◽

Mieneke C. M. Luijendijk-Berg ◽

Azar Omrani ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Substantia Nigra ◽

Ventral Tegmental Area ◽

Food Reward ◽

Leptin Receptor ◽

Ventral Tegmental ◽

Motivational Behavior ◽

Lepr Expression

Leptin is an anorexigenic hormone, important in the regulation of body weight. Leptin plays a role in food reward, feeding, locomotion and anxiety. Leptin receptors (LepR) are expressed in many brain areas, including the midbrain. In most studies that target the midbrain, either all LepR neurons of the midbrain or those of the ventral tegmental area (VTA) were targeted, but the role of substantia nigra (SN) LepR neurons has not been investigated. These studies have reported contradicting results regarding motivational behavior for food reward, feeding and locomotion. Since not all midbrain LepR mediated behaviors can be explained by LepR neurons in the VTA alone, we hypothesized that SN LepR neurons may provide further insight. We first characterized SN LepR and VTA LepR expression, which revealed LepR expression mainly on DA neurons. To further understand the role of midbrain LepR neurons in body weight regulation, we chemogenetically activated VTA LepR or SN LepR neurons in LepR-cre mice and tested for motivational behavior, feeding and locomotion. Activation of VTA LepR neurons in food restricted mice decreased motivation for food reward (p=0.032) and food intake (p=0.020), but not locomotion. In contrast, activation of SN LepR neurons in food restricted mice decreased locomotion (p=0.025), but not motivation for food reward or food intake. Our results provide evidence that VTA LepR and SN LepR neurons serve different functions, i.e. activation of VTA LepR neurons modulated motivation for food reward and feeding, while SN LepR neurons modulated locomotor activity.

Download Full-text

Type 2 Diabetes Mellitus is Associated with Lower Serum Adiponectin Level in Bangladeshi Population

Anwer Khan Modern Medical College Journal ◽

10.3329/akmmcj.v6i1.24978 ◽

2015 ◽

Vol 6 (1) ◽

pp. 10-13

Author(s):

Sohely Nazneen Eva ◽

Rahelee Zinnat ◽

Golam Morshed Molla ◽

Muneera Zahir ◽

Fatema Akter ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adiponectin Level ◽

Serum Insulin ◽

Serum Adiponectin ◽

Enzyme Linked Immunosorbent Assay ◽

Serum Adiponectin Level ◽

Lower Serum ◽

Control Subjects

Background: The physiological role of adiponectin is not yet fully clear, but it is now generally accepted that it has a protective role against the development of lifestyle disorders, related to insulin resistance and atherosclerosis. Insulin resistance is one of the basic defects of type 2 diabetes (T2DM) and adiponectin is inversely associated with T2DM. As serum adiponectin level has not yet been investigated in Bangladeshi T2DM subjects,so that the present study has been under taken to find out the association of T2DM with serum adiponectin level in Bangladeshi population.Methodology: In this observational case control study, sixty six (66) T2DM subjects, seventy four (74) healthy control subjects were included. Diabetes was diagnosed and classified as per WHO criteria. Serum Adiponectin was measured by Enzyme Linked Immunosorbent Assay (ELISA) method. Serum glucose was measured by glucose-oxidase method; serum insulin was measured by chemiluminescence-based ELISA technique. The insulin secretory capacity (HOMA%B), insulin sensitivity (HOMA%S) & insulin resistance (HOMA IR) were assayed by homeostasis model assessment method.Results: The study subjects were BMI matched. BMI of the Control subjects and T2DM subjects (Mean±SD) were 25.02±3.55 and 25.85±3.62. Age (year) of the Control subjects and T2DM subjects (Mean±SD) were 42.46±9.24 and 48.49±8.09. Median (range) fasting serum insulin in the control and T2DM was 14.68 (1.86-45.92) and 18.09 (4.10-42.78) respectively which was not statistically significant (p=0.214). Median (range) HOMA%B values in the control and T2DM subjects was 160.10(33.40-493.40) and 100.45(17.70-349.30). Median HOMA%B in the T2DM group was significantly lower compared to the control (p=0.0001). Median (range) HOMA%S values in the control and T2DM subjects was 44.20(9.80- 339.40) and 32.80(14.30-154.70) respectively. Median HOMA%S in the T2DM group was significantly lower compared to the control (p=0.036). Median (range) serum adiponectin (?g/ml) of the control and T2DM subjects was 8.70 (0.76-15.96) and 6.19 (1.13-22.37). Serum adiponectin was significantly lower in T2DM compared to the control (p=0.0001).Conclusions: From this study it may be concluded that, T2DM subjects have both insulin secretory defects and insulin resistance and associated with lower serum adiponectin level in Bangladeshi population.Anwer Khan Modern Medical College Journal Vol. 6, No. 1: January 2015, Pages 10-13

Download Full-text

Impaired Central Insulin Response in Aged Wistar Rats: Role of Adiposity

Endocrinology ◽

10.1210/en.2007-0543 ◽

2007 ◽

Vol 148 (11) ◽

pp. 5238-5247 ◽

Cited By ~ 34

Author(s):

Miriam García-San Frutos ◽

Teresa Fernández-Agulló ◽

Alain J. De Solís ◽

Antonio Andrés ◽

Carmen Arribas ◽

...

Keyword(s):

Insulin Resistance ◽

Signal Transduction ◽

Body Weight ◽

Food Intake ◽

Insulin Receptor ◽

Food Restriction ◽

Wistar Rats ◽

Insulin Response ◽

Old Rats

Insulin, like leptin, is considered as a lipostatic signal acting at a central level. Aging and age-associated adiposity have been related to the development of leptin resistance in Wistar rats. In the present article, hypothalamic insulin response during aging has been studied in Wistar rats. Thus, the effects of intracerebroventricular infusion of insulin during a week on food intake and body weight as well as insulin signal transduction after acute intracerebroventricular insulin administration have been studied in 3-, 8-, and 24-month-old rats. To explore the possible role of age-associated adiposity, these experiments were also performed in 8- and 24-month-old rats after 3 months of food restriction to reduce visceral adiposity index to values below those of young animals. Intracerebroventricular administration of insulin during a week was more efficient at reducing food intake and body weight in 3-month-old rats than in 8- and 24-month-old rats. Hypothalamic insulin-stimulated insulin receptor, GSK3, AKT, and p70S6K phosphorylation decreased with aging. Insulin receptor and IRS-2 phosphoserine was increased in 24-month-old rats. Food restriction improved both insulin responsiveness and insulin signaling. These data suggest that Wistar rats develop hypothalamic insulin resistance with aging. This can be explained by alterations of the signal transduction pathway. The fact that food restriction improves central insulin response and signal transduction points to the age-associated adiposity as a key player in the development of central insulin resistance.

Download Full-text

Palmitoylated PrRP analog decreases body weight in DIO rats but not in ZDF rats

Journal of Endocrinology ◽

10.1530/joe-15-0519 ◽

2016 ◽

Vol 229 (2) ◽

pp. 85-96 ◽

Cited By ~ 12

Author(s):

Martina Holubová ◽

Jana Zemenová ◽

Barbora Mikulášková ◽

Vladimíra Panajotova ◽

Jiří Stöhr ◽

...

Keyword(s):

Body Weight ◽

Food Intake ◽

Glucose Tolerance ◽

Leptin Receptor ◽

Leptin Resistance ◽

Dependent Manner ◽

Sprague Dawley ◽

Obesity And Diabetes ◽

Diabetes Diet ◽

Zdf Rats

Anorexigenic neuropeptides produced and acting in the brain have the potential to decrease food intake and ameliorate obesity, but are ineffective after peripheral application, owing to a limited ability to cross the blood–brain barrier. We have designed lipidized analogs of prolactin-releasing peptide (PrRP), which is involved in energy balance regulation as demonstrated by obesity phenotypes of bothPrrp-knockout andPrrpreceptor-knockout mice. The aim of this study was to characterize the subchronic effect of a palmitoylated PrRP analog in two rat models of obesity and diabetes: diet-induced obese Sprague–Dawley rats and leptin receptor-deficient Zucker diabetic (ZDF) rats. In the rats with diet-induced obesity (DIO), a two-week intraperitoneal treatment with palmitoylated PrRP lowered food intake by 24% and body weight by 8%. This treatment also improved glucose tolerance and tended to decrease leptin levels and adipose tissue masses in a dose-dependent manner. In contrast, in ZDF rats, the same treatment with palmitoylated PrRP lowered food intake but did not significantly affect body weight or glucose tolerance, probably in consequence of severe leptin resistance due to a nonfunctional leptin receptor. Our data indicate a good efficacy of lipidized PrRP in DIO rats. Thus, the strong anorexigenic, body weight-reducing, and glucose tolerance-improving effects make palmitoylated PrRP an attractive candidate for anti-obesity treatment.

Download Full-text