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PubMed2005

Cardiovascular disease risk factors in habitual exercisers, lean sedentary men and abdominally obese sedentary men.

OBJECTIVE: To investigate whether the favourable cardiovascular disease (CVD) risk factor profile of habitual exercisers is attributable to exercise or leanness. DESIGN: Cross-sectional study of 113 nonsmoking men aged 30-45 y. CVD risk factors were compared in exercisers (n=39) and sedentary men (n=74), and in subgroups of lean exercisers (n=37), lean sedentary men (n=46) and obese sedentary men (n=28). Waist girth was used to identify lean (<100 cm) and abdominally obese (> or =100 cm) subgroups. MEASUREMENTS: Blood pressure, physical activity (7-day recall), physical fitness (maximum oxygen consumption) and fasted lipoproteins, apolipoprotein (apo) B, triglycerides, glucose and fibrinogen. RESULTS: Exercisers were fitter and leaner than sedentary men and had a better CVD risk factor profile. Total cholesterol, LDL-cholesterol and apo B concentrations were lower in lean exercisers than in lean sedentary men, suggesting that exercise influences these risk factors. Indeed, time spent in vigorous activity was the only significant predictor of total cholesterol and LDL-cholesterol in multiple linear regression models. Exercise status had little influence on triglycerides and HDL-cholesterol (HDL-C), and unfavourable levels were only evident among obese sedentary men. Waist girth was the sole predictor of triglycerides and HDL-C, explaining 44 and 31% of the variance, respectively. CONCLUSIONS: These findings suggest that the CVD risk factor profile of habitual exercisers is attributable to leanness and exercise. Leanness is associated with favourable levels of HDL-C and triglycerides, while exercise is associated with lower levels of total cholesterol, LDL-cholesterol and apo B.

Adult↗
PubMed2006

Agouti-related protein promoter variant associated with leanness and decreased risk for diabetes in West Africans.

OBJECTIVE: The role of the central melanocortin system in the development of obesity has been extensively studied. Single-nucleotide polymorphisms (SNPs) within several candidate genes have been associated with food intake and obesity-related phenotypes; however, few of these associations have been replicated. SNPs in the agouti-related protein (AGRP) gene coding (Ala67Thr, 199G/A) and promoter (-38C/T) have been reported to be associated with body mass index (BMI), fat mass (FM) and percent body fat, in populations of European and African descent. In this study, we evaluated the association between the functional AGRP -38C/T promoter SNP and weight-related traits, namely BMI, FM and fat-free mass (FFM), as well as diabetes status. DESIGN: An association study of the AGRP -38C/T SNP and indices of obesity and diabetes status. SUBJECTS: A well-characterized population of 538 West Africans from Ghana and Nigeria recruited in the AADM (Africa America Diabetes Mellitus) study (mean age 52 years, 41.3% males, 71% diabetic). MEASUREMENTS: Genotyping of the AGRP -38C/T SNP, BMI, FM, FFM and fasting plasma glucose. RESULTS: Women carrying two copies of the variant T allele had significantly lower BMI (OR=0.47; 95% CI, 0.25-0.87). Also, men with at least one copy of the variant T allele were over two times less likely to be diabetic than other men (OR=0.44; 95% CI, 0.22-0.89). CONCLUSION: Our results replicate previous findings and implicate the AGRP -38C/T SNP in the regulation of body weight in West Africans.

Agouti Signaling Protein↗
PubMed2006

The role of waist circumference in predicting disability in periretirement age adults.

OBJECTIVE: To measure the risk of periretirement age disability associated with five different anthropometric measures of body mass and shape, and to compare the measures in this group, the peak age group of obesity prevalence. DESIGN: Longitudinal study of Health Survey for England 1998 respondents followed-up in the English Longitudinal Study of Ageing in 2002. SUBJECTS: National population sample of 1030 women and 888 men aged 55-74 years. MEASUREMENTS: Five baseline exposure measures (weight (WT), body mass index (BMI), waist circumference (WC), hip circumference (HC), and waist-hip ratio (WHR)) at baseline, and disability outcomes (measured gait speed, self-reported mobility problems, instrumental and ordinary activities of daily living (I/ADLs)) after 5 years. RESULTS: Individually, the heaviest quartile of WC and WHR predicted disability using all outcomes in men. In women, the heaviest category of each of the five exposure measures predicted disability, for each of the outcomes. In competing measures models, WC was included in the best fit model of tested mobility disability in men (odds ratio (OR) 2.4; 95% confidence interval (CI) 1.4-4.1; P<0.05) and women (OR 3.0; 95% CI 1.9-4.8; P<0.001), adjusted for age, height, smoking, social class, and education. WC was also included in the best fit model of all self-reported disabilities in men, and for self-reported I/ADL disabilities in women. CONCLUSIONS: Across the periretirement age period, body mass and shape are major determinants of disability, with increases in WC, a marker for abdominal obesity, best predicting risk for most disability outcomes. This result adds to the case for WC to be used in estimates of obesity-related health risks for epidemiological monitoring and clinical care.

Activities of Daily Living↗
PubMed2006

A study of central fatness using waist-to-height ratios in UK children and adolescents over two decades supports the simple message--'keep your waist circumference to less than half your height'.

OBJECTIVE: To examine the influence of age and gender on the waist:height ratio (WHTR) in children and to compare changes over time in WHTR, a measure of central fatness in British children. DESIGN: Representative cross-sectional surveys in 1977, 1987 and 1997. SETTING: Great Britain and Northern Ireland. PARTICIPANTS: Survey 1: children aged 5-16 years measured in 1977 (boys) and 1987 (girls) (BSI, n=8135) and Survey 2: children aged 11-16 measured in 1997 (NDNS, n=773). OUTCOME MEASURES: From Survey 1, waist: height ratio related to age and sex and the proportion of children with a WHTR greater than 0.500 (a boundary value suggested for adults). From Survey 2, comparison of WHTR in children with that from Survey 1 and the actual proportion of children with a WHTR greater than 0.500 compared with the expected proportion using the survey 1 as reference. RESULTS: WHTR decreased with age (P<0.01 for trend), with the mean WHTR being significantly lower in girls (P<0.01). WHTR was significantly greater in children in Survey 2 compared with those measured 10 and 20 years earlier in Survey 1 (P<0.0001). The proportion of children where WHTR exceeded the 0.500 boundary value in Survey 2 was 17% of boys and 11.7% of girls (against 5.0 and 1.5%, respectively, in Survey 1, P<0.0001). The increase in WHTR in boys exceeded that in girls. CONCLUSIONS: Values of WHTR during the past 10-20 years have increased greatly showing that central fatness in children has risen dramatically. WHTR is more closely linked to childhood morbidity than body mass index (BMI) and we suggest it should be used as an additional or alternative measure to BMI in children as well as adults. A simple public health message that is the same for adults and children of both sexes and all ages could be stated as 'keep your waist circumference to less than half your height'.

Adipose Tissue↗
PubMed2006

Waist circumference and BMI are independently associated with the variation of cardio-respiratory and neuromuscular fitness in young adult men.

OBJECTIVE: To test two hypotheses: (1) cardiorespiratory (CRF) and neuromuscular (NMF) fitness is associated with body mass index (BMI) and waist circumference (WC), independent of each other and of leisure-time physical activity; (2) individuals with high CRF and NMF have lower WC for a given BMI, compared with those with low CRF and NMF. DESIGN: Cross-sectional study. SETTING: Men participating in refresher training organized by the Finnish Defence Forces. PARTICIPANTS: A total of 951 men (mean age 29.1, s.d. 4.2 years; BMI 25.3 kg/m(2), s.d. 3.8; WC 91, s.d. 11 cm). MAIN OUTCOME MEASURES: Body mass index, WC, maximal oxygen uptake (VO(2)max), height of vertical jump, number of push-ups and sit-ups during a 1-min test, static back extension endurance, isometric grip strength, self-reported leisure-time vigorous physical activity. Multiple linear regressions were used to explain the variation in fitness. RESULTS: Waist circumference had significant (P<0.001) negative association with all test results (standardized beta coefficients from -0.23 to -0.77), except for grip strength. Body mass index had significant negative association with VO(2)max (-0.12; P<0.05), but positive association (P<0.01) with grip strength (0.28), vertical jump (0.21) and push-ups (0.55). For a given BMI, the estimated WC was highest among those with the poorest results for VO(2)max, vertical jump, sit-ups and push-ups. CONCLUSIONS: Despite stronger isometric grip strength, the functional muscle fitness of the upper body, trunk and lower extremities is impaired in individuals with abdominal obesity. Although the known loss of CRF is a serious consequence of obesity, the deterioration of NMF deserves increased attention.

Adult↗
PubMed2006

Weight loss effect on inflammation and LDL oxidation in metabolically healthy but obese (MHO) individuals: low inflammation and LDL oxidation in MHO women.

OBJECTIVE: Recently, a subtype of obesity characterized as a metabolically healthy but obese (MHO) individual has been identified. However, limited data are available on these MHO individuals' metabolic and inflammatory profiles, and the effect of weight loss on these profiles. We investigated metabolic and inflammatory markers in MHO women to determine the effects of a 12-week weight loss on those markers. SUBJECTS: One hundred and twenty-nine overweight-obese Korean women participated for 12 weeks in a clinical intervention study involving a 300 kcal/day intake reduction. The subjects were divided into two groups: MHO and metabolically abnormal obese (MAO) individuals. METHODS: Computed tomography was performed. C-reactive protein (CRP), interkeukin-6 (IL-6) and oxidized low-density lipoprotein (LDL), as well as blood lipids, glucose and insulin concentrations were determined at baseline and after weight loss. RESULTS: At baseline, plasma CRP (P<0.001), IL-6 (P<0.05) and oxidized LDL (P<0.001) levels were significantly lower in the MHO group than in the MAO group. Visceral fat at L1 (P<0.005) and visceral fat at L4 (P<0.001) were significantly lower in the MHO group than in the MAO group. The treatment induced weight loss averaging 3.11% of initial body weight, and the degree of weight loss between the two groups was similar. Visceral fat at L1 and L4 was reduced from its initial values by 3.2 and 5.4%, respectively, after weight loss. The levels of CRP (P<0.05) and oxidized LDL (P<0.01) were significantly reduced in the MAO group after the 12-week weight loss, whereas these effects were not seen in the MHO group. CONCLUSIONS: Our results showed that MHO individuals exhibited lower visceral fat accumulation and more favorable metabolic and inflammatory states than MAO individuals. After a 12-week weight loss program, significant reductions in blood lipids, CRP and oxidized LDL levels were observed in MAO individuals. However, there was no measurable effect of weight loss on lipid profiles and inflammation in MHO individuals, indicating differing effects of weight loss on these markers between MAO and MHO groups.

Abdomen↗
PubMed2006

The thrifty 'catch-up fat' phenotype: its impact on insulin sensitivity during growth trajectories to obesity and metabolic syndrome.

The analyses of large epidemiological databases have suggested that infants and children who show catch-up growth, or adiposity rebound at a younger age, are predisposed to the development of obesity, type 2 diabetes and cardiovascular diseases later in life. The pathophysiological mechanisms by which these growth trajectories confer increased risks for these diseases are obscure, but there is compelling evidence that the dynamic process of catch-up growth per se, which often overlaps with adiposity rebound at a younger age, is characterized by hyperinsulinemia and by a disproportionately higher rate in the recovery of body fat than lean tissue (i.e. preferential 'catch-up fat'). This paper first focuses upon the almost ubiquitous nature of this preferential 'catch-up fat' phenotype across the life cycle as a risk factor for obesity and insulin-related complications - not only in infants and children who experienced catch-up growth after earlier fetal or neonatal growth retardation, or after preterm birth, but also in adults who show weight recovery after substantial weight loss owing to famine, disease-cachexia or periodic dieting. It subsequently reviews the evidence indicating that such preferential catch-up fat is primarily driven by energy conservation (thrifty) mechanisms operating via suppressed thermogenesis, with glucose thus spared from oxidation in skeletal muscle being directed towards de novo lipogenesis and storage in white adipose tissue. A molecular-physiological framework is presented which integrates emerging insights into the mechanisms by which this thrifty 'catch-up fat' phenotype crosslinks with early development of insulin and leptin resistance. In the complex interactions between genetic constitution of the individual, programming earlier in life, and a subsequent lifestyle of energy dense foods and low physical activity, this thrifty 'catch-up fat' phenotype--which probably evolved to increase survival capacity in a hunter-gatherer lifestyle of periodic food shortages--is a central event in growth trajectories to obesity and to diseases that cluster into the insulin resistance (metabolic) syndrome.

Adiposity↗
PubMed2003

White adipose tissue: getting nervous.

Neuroendocrine research has altered the traditional perspective of white adipose tissue (WAT) as a passive store of triglycerides. In addition to fatty acids, WAT produces many hormones and can therefore be designated as a traditional endocrine gland actively participating in the integrative physiology of fuel and energy metabolism, eating behaviour and the regulation of hormone secretion and sensitivity. WAT is controlled by humoral factors, para- and intracrine factors and by neural regulation. Sympathetic nerve fibres innervate WAT and stimulate lipolysis, leading to the release of glycerol and free fatty acids. In addition, recent research in rats has clearly shown a functional parasympathetic innervation of WAT. There appears to be a distinct somatotopy within the parasympathetic nuclei: separate sets of autonomic neurones in the brain stem innervate either the visceral or the subcutaneous fat compartment. We therefore propose that the central nervous system (CNS) plays a major role in the hitherto unexplained regulation of body fat distribution. Parasympathectomy induces insulin resistance with respect to glucose and fatty acid uptake in the innervated fat depot and has selective effects on local hormone synthesis. Thus, the CNS is involved not only in the regulation of hormone production by WAT, but also in its hormone sensitivity. The developments in this research area are likely to increase our insights in the pathogenesis of metabolic disorders such as hypertriglyceridemia, diabetes mellitus type 2 and lipodystrophy syndromes.

Adaptation, Physiological↗
PubMed2006

Gender and elevated albumin excretion in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort: role of central obesity.

BACKGROUND: Microalbuminuria (MA), a predictor of cardiovascular disease in subjects without diabetes and with type 2 diabetes, is more common in men than women in some studies. MA has been linked to central obesity-related traits, including increased waist-hip ratio (WHR), suggesting visceral adiposity might contribute to elevated albumin excretion rate (AER). These relationships have been examined less thoroughly in patients with type 1 diabetes. METHODS: We examined the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications database obtained 4 years after the end of the DCCT to determine whether sex was related to AER in patients with type 1 diabetes and how WHR, a surrogate for visceral adiposity, affected the sex-MA relationship. We fitted models with ln(AER) as the response, adjusted for age, hemoglobin A1c level, smoking status, diabetes duration, and blood pressure, plus WHR, body mass index (BMI), or sex, alone or in combination. RESULTS: Men had greater AERs. WHR was associated with AER, whereas neither sex nor BMI alone was associated with AER when adjusted for WHR. For women, but not men, AER was associated with waist circumference. CONCLUSION: Sex is associated with AER in patients with type 1 diabetes, a relationship accounted for by WHR, consistent with a role for visceral adiposity in this process. Whether this observation is caused by a direct effect of sex hormones on the kidney and WHR or the effect of sex hormones on body fat distribution leading to differences in AER remains to be determined.

Adult↗
PubMed2000

The genetics of sleep apnea.

Obstructive sleep apnea hypopnea syndrome (OSAHS) is a complex chronic condition that is undoubtedly influenced by multiple factors. Accumulating data suggest that there are strong genetic underpinnings for this condition. It has been estimated that approximately 40% of the variance in the apnea hypopnea index (AHI) may be explained by familial factors. It is likely that genetic factors associated with craniofacial structure, body fat distribution and neural control of the upper airway muscles interact to produce the OSAHS phenotype. Although the role of specific genes that influence the development of OSAHS have not yet been identified, current research in rodents suggests that several genetic systems may be important. In this chapter, we shall first define the OSAHS phenotype, and then review the evidence that suggests an underlying genetic basis of OSAHS, the risk factors for OSAHS that may be inherited, and potential candidate genes.

Journal Article↗
PubMed2001

Recombinant human growth hormone, but not insulin-like growth factor-I, enhances central fat loss in postmenopausal women undergoing a diet and exercise program.

We examined the effect of recombinant human growth hormone (rhGH) and/or recombinant human insulin-like growth factor-I (rhIGF-l) on regional fat loss in postmenopausal women undergoing a weight loss regimen of diet plus exercise. Twenty-seven women aged 59-79 years, 20-40% above ideal body weight, completed a 12-week program consisting of resistance training 2 days/week and walking 3 days/week, while consuming a diet that was 500 kcal/day less than that required for weight maintenance. Participants were randomly assigned in a double-blind fashion to receive rhGH (0.025 mg/kg BW/day; n = 7), rhIGF-I (0.015 mg/kg BW/day; n = 7), rhGH + rhIGF-I (n = 6), or placebo (PL; n = 7). Regional and whole body fat mass were determined by dual X-ray absorptiometry. Body fat distribution was assessed by the ratios of trunk fat-to-limb fat (TrF/LimbF) and trunk fat-to-total fat (TrF/TotF). Limb and trunk fat decreased in all groups (p < 0.01). For both ratios of fat distribution, the rhGH treated group experienced an enhanced loss of truncal compared to peripheral fat (p < 0.01), with no significant change for those administered rhIGF-I or PL. There was no association between change in fat distribution and indices of cardiovascular disease risk as determined by serum lipidilipoprotein levels and maximal aerobic capacity. These results suggest that administration of rhGH facilitates a decrease in central compared to peripheral fat in older women undertaking a weight loss program that combines exercise and moderate caloric restriction, although no beneficial effects are conferred to lipid/lipoprotein profiles. Further, the effect of rhGH is not enhanced by combining rhGH with rhIGF-I administration. In addition, rhIGF-I does not augment the loss of trunk fat when administered alone.

Aged↗
PubMedDate not supplied

Human adipose tissue under in vitro inhibition of 11beta-hydroxysteroid dehydrogenase type 1: differentiation and metabolism changes.

In humans, oxoreducing 11beta-HSD-1 activity appears to be related to body fat distribution in male-type central obesity, but not in female-type peripheral obesity. We postulated that inhibition of 11beta-HSD-1 might have clinical therapeutic significance in oxoreducing mostly visceral fat and its metabolic activity. Our current study investigated the consequence at the cellular level of such inhibition. As an inhibitor of 11beta-HSD-1 activity, we used the licorice derivative carbenoxolone. Carbenoxolone has an inhibitory effect on the activity of both oxidizing 11beta-HSD-2, which converts cortisol to cortisone, and oxoreducing 11beta-HSD-1; yet, preadipocytes and adipocytes only express the latter. Preadipocytes were retrieved from omental and subcutaneous fat from healthy non-obese individuals and differentiated in vitro to mature adipocytes. Activity of 11beta-HSD-1 was assayed by measuring conversion of added 500 nM cortisone to cortisol. Expression of 11beta-HSD-1 mRNA was determined by real-time PCR, while lipolytic effects were determined by measuring glycerol and triglyceride concentration in the culture medium. Carbenoxolone decreased 11beta-HSD-1 activity in a dose-dependent manner with an IC-50 of 5X10 -6 M, but did not affect the expression of 11beta-HSD-1 mRNA. Cortisone stimulated subcutaneous, but not omental preadipocytes proliferation, an effect that was not abolished by carbenoxolone. Dexamethasone had a stimulatory effect on the maturation of both omental and subcutaneous preadipocytes. Carbenoxolone per se, either with or without cortisone, had a negative effect on preadipocyte maturation. Inhibiting 11beta-HSD-1 activity by carbenoxolone had no impact on leptin secretion. Thus, carbenoxolone has no effect on preadipocyte proliferation, but a dramatic inhibitory effect on preadipocyte differentiation into mature adipocytes. The mechanism is only partly related to its inhibitory effect on 11beta-HSD-1 activity. The present observations lend support to the presence of an intracrine loop of a hormone that is both produced from a precursor and active within the preadipocyte and adipocyte.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2006

Serum alanine aminotransferase is associated with serum adiponectin, C-reactive protein and apolipoprotein B in young healthy men.

Several studies have reported an association between markers of liver injury, including elevated concentrations of alanine aminotransferase (ALT) aspartate aminotransferase (AST), and prospective risk of type 2 diabetes. We therefore examined the relationship between ALT and AST on the one hand, and serum adiponectin and highly sensitive CRP on the other, both of which have been reported to be associated with prospective risk of type 2 diabetes; we also tested for variable components of metabolic syndrome in 198 male college students aged 18-20 years. ALT showed a positive relationship with percentage body fat (r = 0.19, p = 0.02), serum leptin (r = 0.21, p = 0.01), LDL cholesterol (r = 0.29, p = 0.0003), triglyceride (r = 0.28, p = 0.0004) and apolipoprotein B (r = 0.35, p < 0.0001) even after adjustment for body mass index (BMI). Although there was a significant relationship with serum insulin, adiponectin (inversely), homeostasis model assessment of insulin resistance, systolic and diastolic blood pressure, HDL cholesterol (inversely) and LDL particle diameter in simple regression analysis, significance disappeared after adjustment for BMI. In contrast, CRP (r = 0.16, p = 0.04) was associated with ALT after adjustment for BMI, although simple regression analysis revealed no association between the two. Relationships were smaller for AST, and significance disappeared after adjustment for BMI. Multiple regression analysis excluding lipid variables revealed significant and independent associations of ALT with adiponectin and percentage body fat. In a model including lipid variables, apolipoprotein B emerged as an independent predictor of ALT in addition to adiponectin and percentage body fat. These variables explained 29 % of ALT variability. In conclusion, serum ALT levels were associated with leptin and CRP as well as many components of the insulin resistance syndrome in young healthy men. Adiponectin, apolipoprotein B and percentage body fat emerged as significant and independent predictors of ALT. Since adiponectin and chronic subclinical inflammation have been reported to predict the development of type 2 diabetes and since abnormalities in apolipoprotein B metabolism occur in the early course of insulin resistance, these findings may be compatible with the association between liver markers and risk of diabetes.

Adiponectin↗
PubMed2006

Alteration of adipocyte metabolism in omega3 fatty acid-depleted rats.

Presently an insufficient supply of long-chain polyunsaturated omega3 fatty acid is prevalent in Western populations leading to potential metabolic consequences. Based on this fact, this study deals mainly with various aspects of lipid metabolism in second generation female omega3-depleted rats. The parametrial fat and body weights were higher in omega3-depleted than control animals. This coincided with liver steatosis but did not alter heart triglyceride/phospholipid ratio. The net uptake of [U-14C] palmitate by adipocytes was also higher in omega3-depleted rats than in control animals. The uptake of D-[U- 4C] glucose or [1,2 (-14)C] acetate by adipocytes was lower, however in omega3-depleted than control animals and was unaffected by insulin in the former as distinct from latter animals. Despite comparable basal lipolysis, the increase in glycerol output from adipocytes provoked by theophylline was higher in omega3-depleted than control rats. The fatty acid pattern of lipids in adipose tissue was characterized in the omega3-depleted rats by a much lower omega3 content, higher apparent Delta 9-saturase and elongase activities, lower efficiency for the conversion of C18:2omega6 to C20:4omega6 and higher efficiency for the conversion of C18:3omega3 to C20:5omega3. These features were compared to those prevailing in liver and plasma lipids. The present study thus extends knowledge on the alteration of lipid metabolism resulting from a deficiency in long-chain polyunsaturated omega3 fatty acids.

Acetates↗
PubMed1986

Hyperinsulinemia in a population at high risk for non-insulin-dependent diabetes mellitus.

The prevalence of non-insulin-dependent diabetes mellitus (NIDDM) is higher in Mexican Americans than in non-Hispanic white Americans, even after adjustment for the former's greater overall and more centralized adiposity. We postulated that this excess risk of NIDDM could be due to resistance to insulin. We performed oral glucose-tolerance tests with measurements of serum insulin concentrations in 225 Mexican Americans and 180 non-Hispanic whites without diabetes as part of the San Antonio Heart Study, a population-based study of risk factors for diabetes. Changes in serum insulin concentrations in response to the glucose challenge were quantified by the area under the serum insulin curve. Overall adiposity was characterized by body-mass index, and regional body-fat distribution by the ratio of subscapular to triceps skinfolds and the ratio of waist to hip circumference. After adjustment for these indicators of adiposity and also for differences in glucose tolerance, Mexican Americans were found to have significantly greater areas under the serum insulin curve than non-Hispanic whites. These data suggest that, like other populations at high risk for NIDDM such as Pima Indians and Micronesians, Mexican Americans have more hyperinsulinemia than can be accounted for by their adiposity.

Adult↗
PubMed2006

Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans.

To elucidate whether the role of leptin in regulating neuroendocrine and immune function during short-term starvation in healthy humans is permissive, i.e., occurs only when circulating leptin levels are below a critical threshold level, we studied seven normal-weight women during a normoleptinemic-fed state and two states of relative hypoleptinemia induced by 72-h fasting during which we administered either placebo or recombinant methionyl human leptin (r-metHuLeptin) in replacement doses. Fasting for 72 h decreased leptin levels by approximately = 80% from a midphysiologic (14.7 +/- 2.6 ng/ml) to a low-physiologic (2.8 +/- 0.3 ng/ml) level. Administration of r-metHuLeptin during fasting fully restored leptin to physiologic levels (28.8 +/- 2.0 ng/ml) and reversed the fasting-associated decrease in overnight luteinizing hormone pulse frequency but had no effect on fasting-induced changes in thyroid-stimulating hormone pulsatility, thyroid and IGF-1 hormone levels, hypothalamic-pituitary-adrenal and renin-aldosterone activity. FSH and sex steroid levels were not altered. Short-term reduction of leptin levels decreased the number of circulating cells of the adaptive immune response, but r-metHuLeptin did not have major effects on their number or in vitro function. Thus, changes of leptin levels within the physiologic range have no major physiologic effects in leptin-replete humans. Studies involving more severe and/or chronic leptin deficiency are needed to precisely define the lower limit of normal leptin levels for each of leptin's physiologic targets.

Adaptation, Physiological↗
PubMed2004

Rapid inhibition of leptin signaling by glucocorticoids in vitro and in vivo.

Elevated secretion of glucocorticoids (GCs) or hypersensitivity to GCs has a permissive effect on the development of obesity and leads to abnormalities of body fat distribution. Recent studies demonstrated GCs act as antagonists of leptin in rodents. However, little is known about the interaction between GCs and leptin signaling. In the present study, we investigated the effects of GCs on leptin action in vitro and in vivo. GCs rapidly inhibited the leptin-induced STAT3 phosphorylation in a dose- and time-dependent manner, as assayed by Western blotting using anti-phosphospecific-STAT3 in human hepatoma cell lines (Huh7) transiently expressing long form leptin receptor. GCs also inhibited the leptin-induced JAK2 tyrosine phosphorylation but unaltered the specific binding of (125)I-leptin to the cells. Parallel experiments, however, demonstrated that the inhibitory effects of GCs were not observed in either IL-6- or LIF-induced STAT3 phosphorylation. Furthermore, we examined the feeding behavior and hypothalamic leptin signaling following intracerebroventricular (icv) infusion of GCs prior to icv leptin infusion in Sprague-Dawley rats. The food intake after 24 h of icv leptin injection increased 3-fold in GCs-treated animals. In addition, central infusion of GCs resulted in a marked reduction of hypothalamic STAT3 phosphorylation in response to icv infusion of leptin. To clarify the molecular mechanism by which GCs rapidly reduce leptin-induced JAK/STAT signaling, we examined the intracellular signal transduction pathway potentially mediated by GCs. PD98059, a specific MEK inhibitor, blocked the inhibitory effects of GCs on leptin-induced JAK/STAT activation in Huh7 cells. These results suggest GCs antagonize leptin action by a rapid inhibition of the leptin-induced JAK/STAT pathway partly via MAPK cascade.

Animals↗
PubMed1999

Phyto-oestrogens: a potential role in the prevention of CHD?

CHD is a major cause of morbidity and mortality in women. The incidence of CHD in premenopausal women is low but increases substantially after the menopause, and this difference suggests that endogenous oestrogens are cardioprotective. Observational prospective studies have consistently shown that exogenous oestrogens also lower CHD risk. The biological mechanisms by which endogenous and exogenous oestrogens exert their protective effect are multifactorial, affecting lipids, carbohydrate metabolism, body fat distribution and blood pressure. The prevention of CHD with oestrogen therapy is therefore aimed both at correction of the traditional risk factors and at direct control of vessel structure and function. The wide international variation in rates of CHD together with the lower mortality in sub-groups of the population suggests that a considerable proportion of CHD may be prevented by dietary modification. Since phyto-oestrogens are structually similar to oestrogen, they have the potential to mimic its effects in vivo. The hypocholesterolaemic effects of soyabean protein (rich in phyto-oestrogen precursors) are well established, but the underlying mechanism and atherogenic potential of these changes are unknown. One isoflavone, genistein, has been shown in vitro to exert effects which may slow the development of atherosclerotic disease. However, further studies are required to determine the dose-related changes induced by phyto-oestrogens on serum lipoproteins, haemostasis and vascular function.

Coronary Disease↗