ENU mutagenesis identifies mice with morbid obesity and severe hyperinsulinemia caused by a novel mutation in leptin

Background

Obesity is a multifactorial disease that arises from complex interactions between genetic predisposition and environmental factors. Leptin is central to the regulation of energy metabolism and control of body weight in mammals.

Methodology/Principal Findings

To better recapitulate the complexity of human obesity syndrome, we applied N-ethyl-N-nitrosourea (ENU) mutagenesis in combination with a set of metabolic assays in screening mice for obesity. Mapping revealed linkage to the chromosome 6 within a region containing mouse Leptin gene. Sequencing on the candidate genes identified a novel T-to-A mutation in the third exon of Leptin gene, which translates to a V145E amino acid exchange in the leptin propeptide. Homozygous Leptin^145E/145E mutant mice exhibited morbid obesity, accompanied by adipose hypertrophy, energy imbalance, and liver steatosis. This was further associated with severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyperleptinemia, characteristics of human obesity syndrome. Hypothalamic leptin actions in inhibition of orexigenic peptides NPY and AgRP and induction of SOCS1 and SOCS3 were attenuated in Leptin^145E/145E mice. Administration of exogenous wild-type leptin attenuated hyperphagia and body weight increase in Leptin^145E/145E mice. However, mutant V145E leptin coimmunoprecipitated with leptin receptor, suggesting that the V145E mutation does not affect the binding of leptin to its receptor. Molecular modeling predicted that the mutated residue would form hydrogen bond with the adjacent residues, potentially affecting the structure and formation of an active complex with leptin receptor within that region.

Conclusions/Significance

Thus, our evolutionary, structural, and in vivo metabolic information suggests the residue 145 as of special function significance. The mouse model harboring leptin V145E mutation will provide new information on the current understanding of leptin biology and novel mouse model for the study of human obesity syndrome.     

Expression Levels of Obesity-Related Genes Are Associated with Weight Change in Kidney Transplant Recipients

Background

The aim of this study was to investigate the association of gene expression profiles in subcutaneous adipose tissue with weight change in kidney transplant recipients and to gain insights into the underlying mechanisms of weight gain.

Methodology/Principal Findings

A secondary data analysis was done on a subgroup (n = 26) of existing clinical and gene expression data from a larger prospective longitudinal study examining factors contributing to weight gain in transplant recipients. Measurements taken included adipose tissue gene expression profiles at time of transplant, baseline and six-month weight, and demographic data. Using multivariate linear regression analysis controlled for race and gender, expression levels of 1553 genes were significantly (p<0.05) associated with weight change. Functional analysis using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes classifications identified metabolic pathways that were enriched in this dataset. Furthermore, GeneIndexer literature mining analysis identified a subset of genes that are highly associated with obesity in the literature and Ingenuity pathway analysis revealed several significant gene networks associated with metabolism and endocrine function. Polymorphisms in several of these genes have previously been linked to obesity.

Conclusions/Significance

We have successfully identified a set of molecular pathways that taken together may provide insights into the mechanisms of weight gain in kidney transplant recipients. Future work will be done to determine how these pathways may contribute to weight gain.     

Expression of Obesity Markers and Persistent Organic Pollutants Levels in Adipose Tissue of Obese Patients: Reinforcing the Obesogen Hypothesis?

Introduction

Persistent Organic Pollutants (POPs) accumulate in adipose tissue and some are described to possess endocrine disrupting capacities. Therefore, it is important to evaluate their effects on key endocrine pathways in adipose tissue (AT), to further evaluate their potential role in metabolic pathologies such as obesity.

Objectives

The aim is twofold: (i) evaluate gene expression levels of obesity marker genes, i.e. the adipokines leptin (LEP), adiponectin (ADIPOQ) and Tumor Necrosis Factor α (TNFα) and the nuclear receptor, Peroxisome Proliferator Activated Receptor γ (PPARγ) in paired subcutaneous (SAT) and visceral (VAT) AT of obese subjects (n = 50) and to relate these values to serum concentrations of LEP and ADIPOQ (ii) evaluate the association of expression levels of marker genes in AT and serum with POP concentrations in AT.

Results and Conclusions

Leptin and adiponectin levels in serum were positively correlated to respectively expression levels of leptin in SAT and adiponectin in VAT. Our study shows more significant correlations between gene expression of obesity marker genes and POP concentrations in VAT compared to SAT. Since VAT is more important than SAT in pathologies associated with obesity, this suggests that POPs are able to influence the association between obesity and the development of associated pathologies. Moreover, this finding reveals the importance of VAT when investigating the obesogen hypothesis. Concerning PPARγ expression in VAT, negative correlations with polychlorinated biphenyls (PCBs) concentrations were found in non T2D patients. LEP serum concentrations correlated with several PCBs in women whereas in men no correlations were found. This strengthens the potential importance of gender differences in obesity and within the obesogen hypothesis.     

Differential Modulation of Arcuate Nucleus and Mesolimbic Gene Expression Levels by Central Leptin in Rats on Short-Term High-Fat High-Sugar Diet

Objective

Leptin resistance is a common hallmark of obesity. Rats on a free-choice high-fat high-sugar (fcHFHS) diet are resistant to peripherally administered leptin. The aim of this study was to investigate feeding responses to central leptin as well as the associated changes in mRNA levels in hypothalamic and mesolimbic brain areas.

Design and Methods

Rats on a CHOW or fcHFHS diet for 8 days received leptin or vehicle intracerebro(lateral)ventricularly (ICV) and food intake was measured 5 h and 24 h later. Four days later, rats were sacrificed after ICV leptin or vehicle and mRNA levels were quantified for hypothalamic pro-opiomelanocortin (POMC) and neuropeptide Y (NPY) and for preproenkephalin (ppENK) in nucleus accumbens and tyrosine hydroxylase (TH) in ventral tegmental area (VTA).

Results

ICV leptin decreased caloric intake both in CHOW and fcHFHS rats. In fcHFHS, leptin preferentially decreased chow and fat intake. Leptin increased POMC and decreased NPY mRNA in CHOW, but not in fcHFHS rats. In CHOW rats, leptin had no effect on ppENK mRNA and decreased TH mRNA. In fcHFHS, leptin decreased ppENK mRNA and increased TH mRNA.

Conclusion

Despite peripheral and arcuate leptin resistance, central leptin suppresses feeding in fcHFHS rats. As the VTA and nucleus accumbens are still responsive to leptin, these brain areas may therefore, at least partly, account for the leptin-induced feeding suppression in rats on a fcHFHS diet.     

Absence of Functional Leptin Receptor Isoforms in the POUND (Leprdb/lb) Mouse Is Associated with Muscle Atrophy and Altered Myoblast Proliferation and Differentiation

Objective

Leptin receptors are abundant in human skeletal muscle, but the role of leptin in muscle growth, development and aging is not well understood. Here we utilized a novel mouse model lacking all functional leptin receptor isoforms (POUND mouse, Lepr^db/lb) to determine the role of leptin in skeletal muscle.

Methods and Findings

Skeletal muscle mass and fiber diameters were examined in POUND mice, and primary myoblast cultures were used to determine the effects of altered leptin signaling on myoblast proliferation and differentiation. ELISA assays, integrated pathway analysis of mRNA microarrays, and reverse phase protein analysis were performed to identify signaling pathways impacted by leptin receptor deficiency. Results show that skeletal muscle mass and fiber diameter are reduced 30–40% in POUND mice relative to wild-type controls. Primary myoblast cultures demonstrate decreased proliferation and decreased expression of both MyoD and myogenin in POUND mice compared to normal mice. Leptin treatment increased proliferation in primary myoblasts from muscles of both adult (12 months) and aged (24 months) wild-type mice, and leptin increased expression of MyoD and myogenin in aged primary myoblasts. ELISA assays and protein arrays revealed altered expression of molecules associated with the IGF-1/Akt and MAPK/MEK signaling pathways in muscle from the hindlimbs of mice lacking functional leptin receptors.

Conclusion

These data support the hypothesis that the adipokine leptin is a key factor important for the regulation of skeletal muscle mass, and that leptin can act directly on its receptors in peripheral tissues to regulate cell proliferation and differentiation.     

Arginase Inhibition Ameliorates Hepatic Metabolic Abnormalities in Obese Mice

Objectives

We examined whether arginase inhibition influences hepatic metabolic pathways and whole body adiposity in diet-induced obesity.

Methods and Results

After obesity induction by a high fat diet (HFD), mice were fed either the HFD or the HFD with an arginase inhibitor, N^ω-hydroxy-nor-L-arginine (nor-NOHA). Nor-NOHA significantly prevented HFD-induced increases in body, liver, and visceral fat tissue weight, and ameliorated abnormal lipid profiles. Furthermore, nor-NOHA treatment reduced lipid accumulation in oleic acid-induced hepatic steatosis in vitro. Arginase inhibition increased hepatic nitric oxide (NO) in HFD-fed mice and HepG2 cells, and reversed the elevated mRNA expression of hepatic genes in lipid metabolism. Expression of phosphorylated 5′ AMPK-activated protein kinase α was increased by arginase inhibition in the mouse livers and HepG2 cells.

Conclusions

Arginase inhibition ameliorated obesity-induced hepatic lipid abnormalities and whole body adiposity, possibly as a result of increased hepatic NO production and subsequent activation of metabolic pathways involved in hepatic triglyceride metabolism and mitochondrial function.     

Leptin Contributes to the Adaptive Responses of Mice to High-Fat Diet Intake through Suppressing the Lipogenic Pathway

Background

Leptin is an adipocyte-derived hormone that plays a critical role in energy homeostasis and lipid metabolism. Overnutrition-associated obesity is known to be accompanied by hyperleptinemia. However, the physiological actions of leptin in the metabolic responses to high-fat diet (HFD) intake remain to be completely elucidated. Here we characterized the metabolic features of mice fed high-fat diets and investigated the impact of leptin upon the lipogenic program which was found to be suppressed by HFD feeding through a proteomics approach.

Results

When maintained on two types of high-fat diets for up to 16 weeks, mice with a higher fat intake exhibited increased body fat accumulation at a greater pace, developing more severely impaired glucose tolerance. Notably, HFD feeding at 4 weeks elicited the onset of marked hyperleptinemia, prior to the occurrence of apparent insulin resistance and hyperinsulinemia. Proteomic analysis revealed dramatically decreased expression of lipogenic enzymes in the white adipose tissue (WAT) from HFD-fed mice, including ATP-citrate lyase (ACL) and fatty acid synthase (FAS). The expression of ACL and FAS in the liver was similarly suppressed in response to HFD feeding. By contrast, HFD-induced downregulation of hepatic ACL and FAS was significantly attenuated in leptin receptor-deficient db/db mice. Furthermore, in the liver and WAT of wild type animals, intraperitoneal leptin administration was able to directly suppress the expression of these two lipogenic enzymes, accompanied by reduced triglyceride levels both in the liver and serum.

Conclusions

These results suggest that leptin contributes to the metabolic responses in adaptation to overnutrition through suppressing the expression of lipogenic enzymes, and that the lipogenic pathway represents a key targeted peripheral component in exerting leptin''s liporegulatory actions.     

Functional evolution of leptin of Ochotona curzoniae in adaptive thermogenesis driven by cold environmental stress

Background

Environmental stress can accelerate the directional selection and evolutionary rate of specific stress-response proteins to bring about new or altered functions, enhancing an organism''s fitness to challenging environments. Plateau pika (Ochotona curzoniae), an endemic and keystone species on Qinghai-Tibetan Plateau, is a high hypoxia and low temperature tolerant mammal with high resting metabolic rate and non-shivering thermogenesis to cope in this harsh plateau environment. Leptin is a key hormone related to how these animals regulate energy homeostasis. Previous molecular evolutionary analysis helped to generate the hypothesis that adaptive evolution of plateau pika leptin may be driven by cold stress.

Methodology/Principal Findings

To test the hypothesis, recombinant pika leptin was first purified. The thermogenic characteristics of C57BL/6J mice injected with pika leptin under warm (23±1°C) and cold (5±1°C) acclimation is investigated. Expression levels of genes regulating adaptive thermogenesis in brown adipose tissue and the hypothalamus are compared between pika leptin and human leptin treatment, suggesting that pika leptin has adaptively and functionally evolved. Our results show that pika leptin regulates energy homeostasis via reduced food intake and increased energy expenditure under both warm and cold conditions. Compared with human leptin, pika leptin demonstrates a superior induced capacity for adaptive thermogenesis, which is reflected in a more enhanced β-oxidation, mitochondrial biogenesis and heat production. Moreover, leptin treatment combined with cold stimulation has a significant synergistic effect on adaptive thermogenesis, more so than is observed with a single cold exposure or single leptin treatment.

Conclusions/Significance

These findings support the hypothesis that cold stress has driven the functional evolution of plateau pika leptin as an ecological adaptation to the Qinghai-Tibetan Plateau.     

Leptin replacement improves cognitive development

Background

Leptin changes brain structure, neuron excitability and synaptic plasticity. It also regulates the development and function of feeding circuits. However, the effects of leptin on neurocognitive development are unknown.

Objective

To evaluate the effect of leptin on neurocognitive development.

Methodology

A 5-year-old boy with a nonconservative missense leptin gene mutation (Cys-to-Thr in codon 105) was treated with recombinant methionyl human leptin (r-metHuLeptin) at physiologic replacement doses of 0.03 mg/kg/day. Cognitive development was assessed using the Differential Ability Scales (DAS), a measure of general verbal and nonverbal functioning; and selected subtests from the NEPSY, a measure of neuropsychological functioning in children.

Principal Findings

Prior to treatment, the patient was morbidly obese, hypertensive, dyslipidemic, and hyperinsulinemic. Baseline neurocognitive tests revealed slower than expected rates of development (developmental age lower than chronological age) in a majority of the areas assessed. After two years, substantial increases in the rates of development in most neurocognitive domains were apparent, with some skills at or exceeding expectations based on chronological age. We also observed marked weight loss and resolution of hypertension, dyslipidemia and hyperinsulinemia.

Conclusions

We concluded that replacement with r-metHuLeptin is associated with weight loss and changes in rates of development in many neurocognitive domains, which lends support to the hypothesis that, in addition to its role in metabolism, leptin may have a cognitive enhancing role in the developing central nervous system.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00659828","term_id":"NCT00659828"}}NCT00659828     

Acute leptin treatment enhances functional recovery after spinal cord injury

Background

Spinal cord injury is a major cause of long-term disability and has no current clinically accepted treatment. Leptin, an adipocyte-derived hormone, is best known as a regulator of food intake and energy expenditure. Interestingly, several studies have demonstrated that leptin has significant effects on proliferation and cell survival in different neuropathologies. Here, we sought to evaluate the role of leptin after spinal cord injury.

Findings

Based on its proposed neuroprotective role, we have evaluated the effects of a single, acute intraparenchymal injection of leptin in a clinically relevant animal model of spinal cord injury. As determined by quantitative Real Time-PCR, endogenous leptin and the long isoform of the leptin receptor genes show time-dependent variations in their expression in the healthy and injured adult spinal cord. Immunohistochemical analysis of post-injury tissue showed the long isoform of the leptin receptor expression in oligodendrocytes and, to a lesser extent, in astrocytes, microglia/macrophages and neurons. Moreover, leptin administered after spinal cord injury increased the expression of neuroprotective genes, reduced caspase-3 activity and decreased the expression of pro-inflammatory molecules. In addition, histological analysis performed at the completion of the study showed that leptin treatment reduced microglial reactivity and increased caudal myelin preservation, but it did not modulate astroglial reactivity. Consequently, leptin improved the recovery of sensory and locomotor functioning.

Conclusions

Our data suggest that leptin has a prominent neuroprotective and anti-inflammatory role in spinal cord damage and highlights leptin as a promising therapeutic agent.     

Weight and metabolic effects of CPAP in obstructive sleep apnea patients with obesity

Background

Obstructive sleep apnea (OSA) is associated with obesity, insulin resistance (IR) and diabetes. Continuous positive airway pressure (CPAP) rapidly mitigates OSA in obese subjects but its metabolic effects are not well-characterized. We postulated that CPAP will decrease IR, ghrelin and resistin and increase adiponectin levels in this setting.

Methods

In a pre- and post-treatment, within-subject design, insulin and appetite-regulating hormones were assayed in 20 obese subjects with OSA before and after 6 months of CPAP use. Primary outcome measures included glucose, insulin, and IR levels. Other measures included ghrelin, leptin, adiponectin and resistin levels. Body weight change were recorded and used to examine the relationship between glucose regulation and appetite-regulating hormones.

Results

CPAP effectively improved hypoxia. However, subjects had increased insulin and IR. Fasting ghrelin decreased significantly while leptin, adiponectin and resistin remained unchanged. Forty percent of patients gained weight significantly. Changes in body weight directly correlated with changes in insulin and IR. Ghrelin changes inversely correlated with changes in IR but did not change as a function of weight.

Conclusions

Weight change rather than elimination of hypoxia modulated alterations in IR in obese patients with OSA during the first six months of CPAP therapy.     

Adiponectin and Leptin Trajectories in Mexican-American Children from Birth to 9 Years of Age

Objectives

To address molecular mechanisms underlying obesity development, we examined patterns of critical metabolism-related hormones, adiponectin and leptin (adipokines), over childhood.

Subjects and Design

Plasma adiponectin and leptin were measured in 80 Mexican-American children at birth and again at 2, 5, and 9 years from the ongoing prospective cohort followed by the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS). We used a mixture modeling approach to identify patterns in adipokine trajectories from birth to 9 years.

Results

Leptin was positively related to child body size within all ages, however adiponectin had inverse and weaker associations with BMI at 2, 5, and 9 years. Correlations between adipokine levels over the 0–2, 2–5, and 5–9-year periods increased for both leptin (r = 0.06, 0.31 and 0.62) and adiponectin (r = 0.25, 0.41 and 0.46). Our mixture modeling approach identified three trajectory clusters for both leptin (1L [slowly-rising], 2L [rapidly-rising], and 3L [stable]) and adiponectin (1A [steep-dropping and rebounding], 2A [moderately-dropping], and 3A [stable]). While leptin groups were most separated over the 2–9-year period, adiponectin trajectories displayed greatest heterogeneity from birth to 2 years. Children in the rapidly-rising 2L group had highest BMI and waist circumference at 9 years. Further, children with greater birth weight had increased odds of belonging to this high risk group (OR = 1.21 95% CI 1.03, 1.43, compared to stable group 3L). Children whose mothers consumed more sugar-sweetened beverages during pregnancy were at risk of being in the steep-dropping 1A group (OR = 1.08, 95% CI 1.01, 1.17, compared to stable group 3A).

Conclusion

Our results highlight developmental differences in leptin and adiponectin over the childhood period. Leptin closely reflects child body size however factors affecting adiponectin and long-term consequences of its changes over infancy need to be further explored.     

Gut Hormones,Appetite Suppression and Cachexia in Patients with Pulmonary TB

Background

Cachexia is a hallmark of pulmonary tuberculosis and is associated with poor prognosis. A better understanding of the mechanisms behind such weight loss could reveal targets for therapeutic intervention. The role of appetite-regulatory hormones in tuberculosis is unknown.

Methods and Findings

41 subjects with newly-diagnosed pulmonary TB (cases) were compared to 82 healthy controls. We measured appetite, body mass index (BMI), % body fat (BF), plasma peptide YY (PYY), leptin, ghrelin, and resistin for all subjects. Measurements were taken at baseline for controls and at treatment days 0, 30, and 60 for cases. Baseline appetite, BMI, and BF were lower in cases than in controls and improved during treatment. PYY, ghrelin, and resistin were significantly elevated in cases and fell during treatment. Leptin was lower in cases and rose with treatment. Appetite was inversely related to PYY in cases. High pre-treatment PYY predicted reduced gains in appetite and BF. PYY was the strongest independent predictor of appetite in cases across all time points.

Conclusions

Appetite-regulatory hormones are altered in TB patients. As hormones normalize during treatment, appetite is restored and nutritional status improves. High baseline PYY is an indicator of poor prognosis for improvement in appetite and nutrition during treatment. Wasting in TB patients may partly be mediated by upregulation of PYY with resulting appetite suppression.     

Hypothalamic Neuroendocrine Circuitry is Programmed by Maternal Obesity: Interaction with Postnatal Nutritional Environment

Objective

Early life nutrition is critical for the development of hypothalamic neurons involved in energy homeostasis. We previously showed that intrauterine and early postnatal overnutrition programmed hypothalamic neurons expressing the appetite stimulator neuropeptide Y (NPY) and suppressor proopiomelanocortin (POMC) in offspring at weaning. However, the long-term effects of such programming and its interactions with post-weaning high-fat-diet (HFD) consumption are unclear.

Research Design and Methods

Female Sprague Dawley rats were exposed to chow or HFD for 5 weeks before mating, throughout gestation and lactation. On postnatal day 1, litters were adjusted to 3/litter to induce postnatal overnutrition (vs. 12 in control). At postnatal day 20, half of the rats from each maternal group were weaned onto chow or HFD for 15 weeks. Hypothalamic appetite regulators, and fuel (glucose and lipid) metabolic markers were measured.

Results

Offspring from obese dams gained more weight than those from lean dams independent of post-weaning diet. Maternal obesity interacted with post-weaning HFD consumption to cause greater levels of hyperphagia, adiposity, hyperlipidemia, and glucose intolerance in offspring. This was linked to increased hypothalamic NPY signaling and leptin resistance in adult offspring. Litter size reduction had a detrimental impact on insulin and adiponectin, while hypothalamic NPY and POMC mRNA expression were suppressed in the face of normal energy intake and weight gain.

Conclusions

Maternal obesity, postnatal litter size reduction and post-weaning HFD consumption caused obesity via different neuroendocrine mechanims. There were strong additive effects of maternal obesity and post-weaning HFD consumption to increase the metabolic disorders in offspring.     

Reversal of obesity and insulin resistance by a non-peptidic glucagon-like peptide-1 receptor agonist in diet-induced obese mice

Background

Glucagon-like peptide-1 (GLP-1) is recognized as an important regulator of glucose homeostasis. Efforts to utilize GLP-1 mimetics in the treatment of diabetes have yielded clinical benefits. A major hurdle for an effective oral therapy has been the difficulty of finding a non-peptidic GLP-1 receptor (GLP-1R) agonist. While its oral bioavailability still poses significant challenges, Boc5, one of the first such compounds, has demonstrated the attainment of GLP-1R agonism in diabetic mice. The present work was to investigate whether subchronic Boc5 treatment can restore glycemic control and induce sustainable weight loss in diet-induced obese (DIO) mice, an animal model of human obesity and insulin resistance.

Methodology/Principal Findings

DIO mice were treated three times a week with Boc5 (0.3, 1 and 3 mg) for 12 weeks. Body weight, body mass index (BMI), food intake, fasting glucose, intraperitoneal glucose tolerance and insulin induced glucose clearance were monitored regularly throughout the treatment. Glucose-stimulated insulin secretion, β-cell mass, islet size, body composition, serum metabolic profiles, lipogenesis, lipolysis, adipose hypertrophy and lipid deposition in the liver and muscle were also measured after 12 weeks of dosing. Boc5 dose-dependently reduced body weight, BMI and food intake in DIO mice. These changes were associated with significant decreases in fat mass, adipocyte hypertrophy and peripheral tissue lipid accumulation. Boc5 treatment also restored glycemic control through marked improvement of insulin sensitivity and normalization of β-cell mass. Administration of Boc5 (3 mg) reduced basal but enhanced insulin-mediated glucose incorporation and noradrenaline-stimulated lipolysis in isolated adipocytes from obese mice. Furthermore, circulating leptin, adiponectin, triglyceride, total cholesterol, nonesterified fatty acid and high-density lipoprotein/low-density lipoprotein ratio were normalized to various extents by Boc5 treatment.

Conclusions/Significance

Boc5 may produce metabolic benefits via multiple synergistic mechanisms and may represent an attractive tool for therapeutic intervention of obesity and diabetes, by means of non-peptidic GLP-1R agonism.     

Association between Serum Leptin Concentrations and Insulin Resistance: A Population-Based Study from China

Background

Insulin resistance contributes to the cardio-metabolic risk. The effect of leptin in obese and overweight population on insulin resistance was seldom reported.

Methods

A total of 1234 subjects (572 men and 662 women) aged ≥18 y was sampled by the procedure. Adiposity measures included BMI, waist circumference, hip circumference, WHR, upper arm circumference, triceps skinfold and body fat percentage. Serum leptin concentrations were measured by an ELISA method. The homeostasis model (HOMA-IR) was applied to estimate insulin resistance.

Results

In men, BMI was the variable which was most strongly correlated with leptin, whereas triceps skinfold was most sensitive for women. More importantly, serum leptin levels among insulin resistant subjects were almost double compared to the subjects who had normal insulin sensitivity at the same level of adiposity in both men and women, after controlling for potential confounders. In addition, HOMA-IR increased significantly across leptin quintiles after adjustment for age, BMI, total energy intake, physical activity and smoking status in both men and women (p for trend <0.0001).

Conclusions

There was a significant association between HOMA-IR and serum leptin concentrations in Chinese men and women, independently of adiposity levels. This may suggest that serum leptin concentration is an important predictor of insulin resistance and other metabolic risks irrespective of obesity levels. Furthermore, leptin levels may be used to identify the cardio-metabolic risk in obese and overweight population.     

Effect of Maternal Body Mass Index on Hormones in Breast Milk: A Systematic Review

Background

Maternal Body Mass Index (BMI) is positively associated with infant obesity risk. Breast milk contains a number of hormones that may influence infant metabolism during the neonatal period; these may have additional downstream effects on infant appetite regulatory pathways, thereby influencing propensity towards obesity in later life.

Objective

To conduct a systematic review of studies examining the association between maternal BMI and the concentration of appetite-regulating hormones in breast milk.

Method

Pubmed was searched for studies reporting the association between maternal BMI and leptin, adiponectin, insulin, ghrelin, resistin, obestatin, Peptide YY and Glucagon-Like Peptide 1 in breast milk.

Results

Twenty six studies were identified and included in the systematic review. There was a high degree of variability between studies with regard to collection, preparation and analysis of breast milk samples. Eleven of fifteen studies reporting breast milk leptin found a positive association between maternal BMI and milk leptin concentration. Two of nine studies investigating adiponectin found an association between maternal BMI and breast milk adiponectin concentration; however significance was lost in one study following adjustment for time post-partum. No association was seen between maternal BMI and milk adiponectin in the other seven studies identified. Evidence for an association between other appetite regulating hormones and maternal BMI was either inconclusive, or lacking.

Conclusions

A positive association between maternal BMI and breast milk leptin concentration is consistently found in most studies, despite variable methodology. Evidence for such an association with breast milk adiponectin concentration, however, is lacking with additional research needed for other hormones including insulin, ghrelin, resistin, obestatin, peptide YY and glucagon-like peptide-1. As most current studies have been conducted with small sample sizes, future studies should ensure adequate sample sizes and standardized methodology.     

Assay of the multiple energy-producing pathways of mammalian cells

Background

To elucidate metabolic changes that occur in diabetes, obesity, and cancer, it is important to understand cellular energy metabolism pathways and their alterations in various cells.

Methodology and Principal Findings

Here we describe a technology for simultaneous assessment of cellular energy metabolism pathways. The technology employs a redox dye chemistry specifically coupled to catabolic energy-producing pathways. Using this colorimetric assay, we show that human cancer cell lines from different organ tissues produce distinct profiles of metabolic activity. Further, we show that murine white and brown adipocyte cell lines produce profiles that are distinct from each other as well as from precursor cells undergoing differentiation.

Conclusions

This technology can be employed as a fundamental tool in genotype-phenotype studies to determine changes in cells from shared lineages due to differentiation or mutation.     

Adipokines,inflammation, insulin resistance,and carotid atherosclerosis in patients with rheumatoid arthritis

Introduction

Cardiovascular (CV) morbidity and mortality are increased in patients with rheumatoid arthritis (RA). Inflammation is thought to be an important factor in accelerated atherosclerosis in RA, whereas insulin resistance is a known risk factor for atherosclerosis in RA. We hypothesised that adipokines could be a link between inflammation, insulin resistance, and atherosclerosis in RA.

Methods

The common carotid artery (CCA) intima-media thickness (IMT), CCA resistive index (RI), and carotid plaques were measured by ultrasonography in 192 patients with RA. Insulin resistance was assessed by the homeostasis model assessment for insulin resistance (HOMA-IR). Serum adiponectin, leptin, resistin, tumor necrosis factor-α, and interleukin (IL)-6 concentrations were determined.

Results

The CCA RI was associated with CCA IMT and the estimated total plaque volume after adjustment for conventional CV risk factors. Among adipokines, resistin and IL-6 were correlated with inflammatory parameters. Leptin and leptin:adiponectin (L:A) ratio were correlated with metabolic risk factors, including HOMA-IR. And L:A ratio was related to the CCA RI after adjustment for conventional and nonconventional CV risk factors, including HOMA-IR, erythrocyte sedimentation rate and C-reactive protein.

Conclusion

L:A ratio was associated with HOMA-IR and carotid RI. L:A ratio might be an independent factor for predicting cardiovascular risk in patients with RA.