Diet-resistant obesity is characterized by a distinct plasma proteomic signature and impaired muscle fiber metabolism.

BACKGROUND/OBJECTIVES: Inter-individual variability in weight loss during obesity treatment is complex and poorly understood. Here we use whole body and tissue approaches to investigate fuel oxidation characteristics in skeletal muscle fibers, cells and distinct circulating protein biomarkers before and after a high fat meal (HFM) challenge in those who lost the most (obese diet-sensitive; ODS) vs the least (obese diet-resistant; ODR) amount of weight in a highly controlled weight management program. SUBJECTS/METHODS: In 20 weight stable-matched ODS and ODR women who previously completed a standardized clinical weight loss program, we analyzed whole-body energetics and metabolic parameters in vastus lateralis biopsies and plasma samples that were obtained in the fasting state and 6 h after a defined HFM, equivalent to 35% of total daily energy requirements. RESULTS: At baseline (fasting) and post-HFM, muscle fatty acid oxidation and maximal oxidative phosphorylation were significantly greater in ODS vs ODR, as was reactive oxygen species emission. Plasma proteomics of 1130 proteins pre and 1, 2, 5 and 6 h after the HFM demonstrated distinct group and interaction differences. Group differences identified S-formyl glutathione hydratase, heat shock 70 kDA protein 1A/B (HSP72), and eukaryotic translation initiation factor 5 (eIF5) to be higher in ODS vs ODR. Group-time differences included aryl hydrocarbon interacting protein (AIP), peptidylpropyl isomerase D (PPID) and tyrosine protein-kinase Fgr, which increased in ODR vs ODS over time. HSP72 levels correlated with muscle oxidation and citrate synthase activity. These proteins circulate in exosomes; exosomes isolated from ODS plasma increased resting, leak and maximal respiration rates in C2C12 myotubes by 58%, 21% and 51%, respectively, vs those isolated from ODR plasma. CONCLUSIONS: Findings demonstrate distinct muscle metabolism and plasma proteomics in fasting and post-HFM states corresponding in diet-sensitive vs diet-resistant obese women.

Variation in C-reactive protein following weight loss in obese insulin resistant postmenopausal women: is there an independent contribution of lean body mass?

BACKGROUND: We showed that obese insulin resistant postmenopausal women are characterized by higher lean body mass and elevated C-reactive protein. Although counterintuitive, we hypothesized that losses in muscle mass following caloric restriction and increase in muscle quality will be associated with improvements in glucose homeostasis through decreases in C-reactive protein. OBJECTIVES: To determine 1) if improvements in C-reactive protein concentrations occurs through losses in lean body mass; and 2) if decreases in C-reactive protein levels contribute to improvements in insulin sensitivity. METHODS: 50 postmenopausal women (body mass index>26 kg/m(²)) with impaired glucose disposal (<7.5 mg/kg/min) completed a 6-month caloric restriction program. Outcome measures were: Glucose disposal rate: M value (by hyperinsulinemic-euglycemic clamp), body composition (total, trunk, and appendicluar). LBM and FM by DXA), LBM index (LBM (kg)/height (m(2)), body fat distribution (VAT and SAT by CT scan) and plasma high-sensitive C-reactive protein (hsCRP) and interleukin-6 (Il-6). RESULTS: Significant correlations were observed between Δ hsCRP levels with Δ Il-6 (r=0.33, p≤0.05), Δ total LBM index (r=0.44, p≤0.01), Δ trunk LBM (r=0.38, p≤0.01) Δ SAT (r=0.35, p≤0.05) and ∆ glucose disposal rate (r=- 0.44, p≤0.01). After including all the correlated variables in Stepwise linear regression model, Δ LBM index was the only independent predictor of the reduction in hsCRP levels (R(2)=0.20, p≤0.01). CONCLUSION: Losses in total lean body mass are independently associated with improvements in inflammatory state (CRP levels) in obese postmenopausal women with impaired glucose disposal.

Persistent organic pollutants meet adipose tissue hypoxia: does cross-talk contribute to inflammation during obesity?

Lipophilic persistent organic pollutants (POPs) accumulate in lipid-rich tissues such as human adipose tissue. This is particularly problematic in individuals with excess adiposity, a physiological state that may be additionally characterized by local adipose tissue hypoxia. Hypoxic patches occur when oxygen diffusion is insufficient to reach all hypertrophic adipocytes. POPs and hypoxia independently contribute to the development of adipose tissue-specific and systemic inflammation often associated with obesity. Inflammation is induced by increased proinflammatory mediators such as tumour necrosis factor-alpha, interleukin-6, and monocyte chemotactic protein-1, as well as reduced adiponectin release, an anti-inflammatory and insulin-sensitizing adipokine. The aryl hydrocarbon receptor (AhR) mediates the cellular response to some pollutants, while hypoxia responses occur through the oxygen-sensitive transcription factor hypoxia-inducible factor (HIF)-1. There is some overlap between the two signalling pathways since both require a common subunit called the AhR nuclear translocator. As such, it is unclear how adipocytes respond to simultaneous POP and hypoxia exposure. This brief review explores the independent contribution of POPs and adipose tissue hypoxia as factors underlying the inflammatory response from adipocytes during obesity. It also highlights that the combined effect of POPs and hypoxia through the AhR and HIF-1 signalling pathways remains to be tested.

Dietary practices in isolated First Nations communities of northern Canada: combined isotopic and lipid markers provide a good qualitative assessment of store-bought vs locally harvested foods consumption.

OBJECTIVE: In First Nations communities of northwestern Ontario, where rates of type 2 diabetes mellitus are some of the highest in the world, ascertaining wild food dietary practices is extremely challenging owing to seasonal availability, environmental factors, life circumstances and language/cultural barriers. The purpose of this study was to determine whether analysis of isotopic and fatty acid (FA) profiles could provide more comprehensive information to discriminate between three categories of wild food consumption (that is, plants and animals) in two isolated First Nations communities of northwestern Ontario. In addition, this analysis also highlights whether wild food consumption as practiced in these two communities can increase circulating levels of polyunsaturated FAs (PUFAs), which provide a number of important metabolic benefits that could impact the prevention/treatment of T2DM. RESULTS: (13)C enrichment (in expired CO2, plasma and hair), (15)N enrichment (in hair) and FA profiles in plasma phospholipids (phospholipid fatty acid (PL-FA)) were quantified in men and in women consuming various amounts of wild food. (13)C/(12)C ratios were lower and (15)N/(14)N ratios were higher in participants consuming wild food at least once a week. In addition, FA results indicated that the relative contributions of 20:4 Ω-6 and 22:6 Ω-3 to total PL-FAs were higher and 18:2 Ω-6 lower in wild food consumers. CONCLUSION: Together, these findings confirm that isotopic and lipid markers discriminate between the different wild food categories in these two First Nations communities. Knowing the close relationship between dietary intake and the potential role of PUFA in the prevention/treatment of obesity and obesity-related diseases, it is critical to accurately measure the composition of diet for individuals in their specific environments.

Weight loss and regain in obese individuals: a link with adipose tissue metabolism indices?

This study was performed to examine whether changes in subcutaneous adipose tissue (SCAT) metabolism indices after weight loss were related to the magnitude of weight regain. Nine men and ten premenopausal women whose body mass index ranged from 30 to 42 kg/m(2), 35-48 years old, were studied before and after a 15-week weight loss program, as well as at a 17-22-month follow-up period. Although body composition was evaluated at all study periods, abdominal and femoral SCAT-lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) activities, and Alpha2- and Beta-adrenoceptors (ARs) were measured before and after weight loss, exclusively. Although the SCAT-LPL activity did not change after weight loss in men, it tended to decrease in the femoral depot of women (p = 0.06). SCAT-HSL activity remained unchanged after weight reduction in men, while the post-weight loss lipase activity tended to be higher in both regions of women (p = 0.06). Although the post-weight loss number of β-ARs was higher irrespective of the fat depot (0.001 < p < 0.05), the number of Alpha2-ARs was increased in the femoral (p < 0.05), but not in the abdominal SCAT (p = 0.08) after weight reduction, in men. Neither the Alpha2- nor the Beta-AR density changed after weight reduction, in women. Abdominal SCAT-LPL activity after weight reduction was negatively related to weight regain indices, in women (-0.65 < Rhô < -0.75; 0.01 < p < 0.05). Both the post-weight loss abdominal SCAT Alpha 2-AR density and the Alpha 2-/Beta-AR balance were positively associated with weight regain indices, in men (0.69 < Rhô < 0.88; 0.01 < p < 0.05). These results suggest that selected SCAT metabolism indices could predict failure to weight loss maintenance, in both genders

The association of type 2 diabetes and insulin resistance/secretion with persistent organic pollutants in two First Nations communities in northern Ontario.

AIMS: Recent evidence suggests an association between persistent organic pollutants (POPs) and type 2 diabetes. In two First Nations communities where wild food is consumed by a large portion of the population, we compared pollutants in plasma between diabetic and non-diabetic individuals, and investigated the strength of association between pollutants and insulin resistance/secretion in non-diabetic individuals. METHODS: The study population consisted of 72 participants. Oral Glucose Tolerance Tests were used to assess diabetes status. Plasma was used to determine POP concentrations and mercury concentrations were determined from hair samples. RESULTS: Age-adjusted plasma concentrations of some pollutants were significantly higher in diabetic than in non-diabetic individuals. When taking into account age, adiposity levels, and smoking status, POP levels were not associated with insulin resistance nor with insulin secretion in non-diabetic individuals. CONCLUSIONS: These findings confirm that POP concentrations in plasma may be higher in diabetic than in non-diabetic individuals. No association was however seen between POP concentrations and markers of insulin resistance/secretion in non-diabetic individuals.

Weight loss and regain in obese individuals: a link with adipose tissue metabolism indices?

This study was performed to examine whether changes in subcutaneous adipose tissue (SCAT) metabolism indices after weight loss were related to the magnitude of weight regain. Nine men and ten premenopausal women whose body mass index ranged from 30 to 42 kg/m(2), 35-48 years old, were studied before and after a 15-week weight loss program, as well as at a 17-22-month follow-up period. Although body composition was evaluated at all study periods, abdominal and femoral SCAT-lipoprotein lipase (LPL) and hormone-sensitive lipase (HSL) activities, and α2- and ß-adrenoceptors (ARs) were measured before and after weight loss, exclusively. Although the SCAT-LPL activity did not change after weight loss in men, it tended to decrease in the femoral depot of women (p = 0.06). SCAT-HSL activity remained unchanged after weight reduction in men, while the post-weight loss lipase activity tended to be higher in both regions of women (p = 0.06). Although the post-weight loss number of ß-ARs was higher irrespective of the fat depot (0.001 < p < 0.05), the number of α2-ARs was increased in the femoral (p < 0.05), but not in the abdominal SCAT (p = 0.08) after weight reduction, in men. Neither the α2- nor the ß-AR density changed after weight reduction, in women. Abdominal SCAT-LPL activity after weight reduction was negatively related to weight regain indices, in women (-0.65 < Rhô < -0.75; 0.01 < p < 0.05). Both the post-weight loss abdominal SCAT α2-AR density and the α2-/ß-AR balance were positively associated with weight regain indices, in men (0.69 < Rhô < 0.88; 0.01 < p < 0.05). These results suggest that selected SCAT metabolism indices could predict failure to weight loss maintenance, in both genders.

Obesity and type 2 diabetes in Northern Canada's remote First Nations communities: the dietary dilemma.

First Nations populations in Northwestern Ontario have undergone profound dietary and lifestyle transformations in less than 50 years, which have contributed to the alarming rise in obesity and obesity-related diseases, in particular type 2 diabetes mellitus. Even though the genetic background of First Nations peoples differs from that of the Caucasians, genetics alone cannot explain such a high prevalence in obesity and type 2 diabetes. Modifications in lifestyle and diet are major contributors for the high prevalence of chronic diseases. What remains constant in the literature is the persistent view that locally harvested and prepared foods are of tremendous value to First Nations peoples providing important health and cultural benefits that are increasingly being undermined by western-based food habits. However, the complexities of maintaining a traditional diet require a multifaceted approach, which acknowledges the relationship between benefits, risks and viability that cannot be achieved using purely conventional medical and biological approaches. This brief review explores the biological predispositions and potential environmental factors that contribute to the development of the high incidence of obesity and obesity-related diseases in First Nations communities in Northern Canada. It also highlights some of the complexities of establishing exact physiological causes and providing effective solutions.

Effects of acute hyperinsulinaemia on total and high-molecular-weight adiponectin concentration in metabolically healthy but obese postmenopausal women: a Montreal-Ottawa New Emerging Team (MONET) study.

AIM: The aim of this study was to determine the differences and changes in total and high-molecular-weight (HMW) adiponectin levels among metabolically healthy but obese (MHO) postmenopausal women in response to acute hyperinsulinaemia. METHOD: In this cross-sectional study, 55 non-diabetic overweight and obese postmenopausal women underwent a hyperinsulinaemic-euglycaemic clamp test to evaluate insulin sensitivity. Subjects within the upper tertile of insulin sensitivity were described as 'MHO' (n=18), whereas those within the lowest tertile were considered 'at risk' (n=18). Plasma total and HMW adiponectin levels were measured by ELISA at 0 (baseline), 90, 160 and 180 min during the clamp. RESULTS: At baseline and at all time points during the clamp, MHO individuals had significantly higher total and HMW adiponectin levels than at-risk subjects (AUC: total adiponectin=2506 ± 1010 vs 1616 ± 830; HMW adiponectin=909 ± 307 vs 604 ± 349; P<0.05). In addition, a significant reduction in total adiponectin was observed at 160 min and 180 min in at-risk and MHO subjects, respectively, while HMW adiponectin significantly decreased at 160 min in at-risk subjects, and at 90 min as well as 160 min in MHO women. CONCLUSION: MHO postmenopausal women had higher levels of plasma total and HMW adiponectin than at-risk subjects at baseline and during the clamp. Furthermore, significant decreases in total and HMW adiponectin were observed at certain time points in both the MHO and at-risk subjects.

Similar associations of total adiponectin and high molecular weight adiponectin with cardio-metabolic risk factors in a population of overweight and obese postmenopausal women: a MONET study.

The aim of the study was to examine the association between total adiponectin and high molecular weight (HMW) adiponectin levels with cardio-metabolic risk factors in a population of sedentary, overweight, and obese postmenopausal women. Cross-sectional study was carried out on 55 nondiabetic sedentary overweight and obese postmenopausal women aged between 50 and 70 years. Insulin sensitivity was assessed by euglycemic-hyperinsulinemic clamp technique. Body composition and visceral fat were measured using dual X-ray absorptiometry and computed tomography, respectively. Other cardio-metabolic risk factors included: plasma lipids, hsC-reactive protein, energy expenditure (doubly labeled water), peak oxygen consumption, muscle strength (using weight training equipment) as well as total and HMW adiponectin. Correlations of total and HMW adiponectin with various cardio-metabolic risk factors were comparable. In addition, regression analysis results showed similar independent predictors of total and HMW adiponectin. Finally, the receiver operator characteristic (ROC) curves for total and HMW adiponectin to predict insulin sensitivity showed no difference between the areas under curve (AUC) (AUC total adiponectin=0.80 [95% CI: 0.66-0.95] versus AUC HMW adiponectin=0.76 [95% CI: 0.60-0.91], p=0.36). The present study indicates that HMW adiponectin does not seem to provide additional information than total adiponectin in relation to cardio-metabolic risk factors in overweight/obese postmenopausal women.

Thermogenesis and weight loss in obese individuals: a primary association with organochlorine pollution.

The main objective of this study was to investigate the potential impact of body organochlorine (OC) pollution on the adaptive change in thermogenesis induced by body weight loss. Fat mass (FM), fat-free mass (FFM), and sleeping metabolic rate (SMR) were measured in obese individuals before and after a weight-reducing program. The measured values of SMR were then compared to those predicted from a reference equation established from FM and FFM in control subjects. Plasma OC, leptin, total tri-iodothyronine, and free thyroxine concentrations were also measured in obese subjects before and after weight loss. After weight loss, the measured decrease in SMR was greater than that predicted by changes in FM and FFM. Increased plasma OC concentration was the factor explaining the greatest proportion of the difference between predicted and measured SMR changes induced by body weight loss. OC pollution seems to be a new factor affecting the control of thermogenesis in some obese individuals experiencing body weight loss.

Energy balance and pollution by organochlorines and polychlorinated biphenyls.

Organochlorines are fat-soluble chemical compounds resistant to degradation, so they are stored in the adipose tissue of practically every organism on the planet, including humans. Accumulation of these compounds in the body seems to be related to fat mass, obese individuals having a higher plasma organochlorine concentration than lean subjects. During body weight loss, lipid mobilization and a decrease in fat mass result in increased concentrations of organochlorines in plasma and adipose tissue. Organochlorines may have adverse health effects. For example, they have been associated with altered immune and thyroid functions and with some types of cancer. As these compounds may reach their target organs whilst in the circulation, their increase in plasma during weight loss might be associated with some physiological changes occurring during weight loss. Relationships have indeed been reported among weight loss-induced increase in plasma organochlorine concentration and decreased triiodothyronine (T3) concentration, resting metabolic rate, and skeletal muscle markers for fat oxidation. Although further studies are needed to assess the causality of these relationships, they raise concern about some potential undesirable effects of weight loss. Indeed, the effects of organochlorines on energy balance could complicate body weight loss and even favour weight regain. These notions lend support for weight-loss strategies favouring a moderate weight loss, which would reduce risks for cardiovascular diseases, diabetes and hypertension, without resulting in a substantial release of organochlorines.

Reduction of visceral adipose tissue during weight loss.

OBJECTIVE: The aims of the present study were to retrospectively: (1) compare how weight loss affects the reduction of adipose tissue from three different sites between men and women; and (2) to verify whether gender differences in the reduction of adipose tissue are influenced by changes in fat mass (FM) and initial levels of fat in different compartments. DESIGN: Double-blind randomized treatment with fenfluramine once daily coupled to a non-macronutrient specific energy restriction. SUBJECTS: Seventeen obese men (age 43.9+/-1.5 and body mass index (BMI) 34.3+/-0.7) and 17 obese women (age 41.2+/-1.2 and BMI 35.7+/-0.6). INTERVENTIONS: Subjects were given fenfluramine (60 mg) or placebo once daily and were also subjected to a non-macronurient specific energy restriction of -2.9 MJ/day (-700 kcal/day) for 15 weeks. RESULTS: Body weight, FM, fat-free mass (FFM), waist circumference, BMI, as well as visceral (VAT), subcutaneous abdominal (SAT) and thigh (TAT) adipose tissue were all significantly reduced. Men lost significantly more VAT (-41.6%) than SAT (-22.5%), or than TAT (-20.5%) while no site difference in fat loss was observed in women when changes were calculated as a percentage of initial levels. Men lost about twice as much fat from the VAT compartment than did women (P<0.05), even after having considered changes in FM as a potential covariate. In absolute values, TAT was reduced to a lesser extent in men than in women. However, when initial levels of respective fat depots were also taken into account, gender differences in VAT and TAT loss were no longer statistically significant. CONCLUSION: These results suggest that gender differences in VAT reduction during weight loss are independent of changes in FM. However, once initial levels of VAT are also taken into account, gender differences in the reduction of this tissue during weight loss are no longer apparent.

Increase in plasma pollutant levels in response to weight loss is associated with the reduction of fasting insulin levels in men but not in women.

Environmental pollutants can act as endocrine modulators. In this study, we examined whether weight loss-induced changes in plasma organochlorine compounds (OC) were associated with those in plasma insulin levels. Fasting insulin and the area under the curve (AUC) of insulin after a 75-g oral glucose load, plasma levels of 1 commercial polychlorinated biphenyl (PCB) mixture (Aroclor 1260), 1 PCB congener (PCB 153), and 3 pesticides (2,2'-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE), beta-hexachlorocyclohexane (beta-HCH), and hexachlorobenzene (HCB)) were measured before and after a 15-week weight loss program induced by a caloric restriction in a sample of obese men and women. Both genders showed a similar reduction in body weight (approximately 11 kg) in response to treatment, although men lost significantly more fat mass than women (mean +/- SD 9.4 +/- 4.1 v 5.9 +/- 5 kg, respectively, P <.05). Fasting insulin and AUC of insulin significantly decreased in men and women after the treatment. In response to weight loss, a significant increase in OC was observed in both genders, and this effect was more pronounced in men. The greater the increase in plasma OC levels, the greater the reduction in fasting insulin was in response to weight loss in men (-.49 < r < -.59, P <.05), but not in women (-.22 < r <.01, not significant [NS]). In both genders, no relationship was observed between changes in plasma OC levels and changes in AUC of insulin (-.41 < r < -.08, NS). In men, relationships between changes in plasma HCB, Aroclor 1260, and PCB-153 concentrations and those in fasting insulin levels in response to weight loss remained significantly correlated after correction for fat mass loss (-.46 < partial r < -.51, P values ranging from.05 to.07). These results suggest that weight loss-induced increase in plasma pollutant levels tends to be independently associated with the reduction of fasting insulin levels in men, but not in women. Further studies are needed to verify whether these findings are causally related.

Increase in plasma pollutant levels in response to weight loss in humans is related to in vitro subcutaneous adipocyte basal lipolysis.

OBJECTIVE: To examine whether weight loss-induced changes in in vitro basal lipolysis of subcutaneous abdominal and femoral fat cells were related to those in plasma organochlorine levels. DESIGN: A 15 week weight loss program induced by a moderate caloric restriction. SUBJECTS: Seventeen men and 20 women (age 36-50 y, body fat 25-50%). MEASUREMENTS: In vitro basal lipolysis of subcutaneous abdominal and femoral adipocytes and plasma levels of five polychlorinated biphenyl congeners (Aroclor 1260, PCBs 118, 138, 153 and 180) and three chlorinated pesticides (dichlorodiphenyl dichloroethene (p,p'-DDE), beta-hexachlorocyclohexane (beta-HCH) and hexachlorobenzene (HCB)) were measured before and after the weight reducing program. RESULTS: Both genders showed a similar reduction in body weight (approximately 11 kg) in response to treatment, although men lost significantly more fat mass than women (mean+/-s.d., 9.4+/-4.1 vs 5.9+/-5 kg, respectively, P<0.05). Mean basal fat cell lipolysis did not vary before and after weight reduction, regardless of depots and genders. In response to weight loss, significant increases of all organochlorines investigated were observed in men, whereas only p,p'-DDE, Aroclor 1260, PCBs 153 and 180 significantly rose in women. In men, higher the increase in basal lipolysis of subcutaneous abdominal or femoral adipocytes, greater the rise in plasma levels of most pollutants (HCB, Aroclor 1260, PCBs 118, 138 and 153) was in response to weight loss (0.51

Difference in leptin response to a high-fat meal between lean and obese men.

The aim of this study was to compare the leptin responses to a high-fat meal in lean and obese men, and to investigate whether the net leptin response (area under the incremental curve) after the meal was related to the thermic effect of food (TEF). Blood samples were collected after an overnight fast and every 2 h for 8 h after a high-fat breakfast (60 g of fat/m(2) body surface area) in 12 lean and 12 obese men for determination of glucose, insulin and leptin. The TEF was calculated as postprandial energy expenditure minus fasting energy expenditure, as measured by indirect calorimetry. Fasting plasma glucose levels were similar in lean and obese men, and increased in the same way after the meal. Fasting and postprandial plasma insulin concentrations were significantly greater in obese than in lean men (P<0.01 and P<0.05 respectively). Accordingly, obese men showed a significantly higher net insulin response than lean subjects (P<0.001). Fasting plasma leptin levels were greater in obese than in lean men (P<0.001). After the meal, plasma leptin increased significantly in lean men, whereas it decreased in obese men (group by time interaction, P<0.01). The net response of leptin was greater in lean than in obese men, but this did not reach statistical significance (P=0.07). Moreover, the TEF was similar in the two groups. No significant relationship was observed between either the net insulin response or the net leptin response after the high-fat meal and the TEF of lean subjects (-0.05

Elevated intramyocellular lipid concentration in obese subjects is not reduced after diet and exercise training.

To determine the effects of weight loss on intramyocellular energy substrates, vastus lateralis muscle biopsies were taken from six obese subjects (body mass index 34 +/- 5 kg/m(2)) before, after 15 wk of energy restriction (ER; -700 kcal/day), and after a further average 20.7 +/- 1.6 wk of endurance training plus low-fat diet (ET-LFD). Body weight fell from 100 +/- 6 to 89 +/- 6 kg during ER and to 84 +/- 4 kg after ET-LFD. Lipids and glycogen were histochemically measured in type I, IIA, and IIB fibers. Total muscle glycogen content (MGC; per 100 fibers) decreased after ER [from 72 +/- 13 to 55 +/- 8 arbitrary units (AU)]. A similar but not significant decrease was seen in total muscle lipid content (MLC; 14 +/- 5 to 9 +/- 1 AU). After ET-LFD, MGC returned to initial values (74 +/- 8 AU), and MLC approached near-initial values (12 +/- 3 AU). Individual fiber lipid concentration did not change throughout the protocol in all fiber types, whereas glycogen concentration increased after ET-LFD. The training effects of ET-LFD were measured as increasing activities of key mitochondrial enzymes. Although total muscle energy reserves can be reduced after weight loss, their concentration within individual myofibers remains elevated. Weight loss does not appear sufficient to correct the potential detrimental effects of high intracellular lipid concentrations.

Age-related differences in messenger ribonucleic acid expression of key proteins involved in adipose cell differentiation and metabolism.

This study was performed to compare the expression of key proteins [lipoprotein lipase (LPL), hormone-sensitive lipase (HSL), complement 3 (C3), and peroxisome proliferator-stimulated receptor-gamma (PPAR gamma)] involved in sc abdominal adipose tissue (AT) metabolism of young (n = 13) vs. middle-aged (n = 16) men. The sc abdominal AT-LPL activity as well as fat cell lipolysis were also measured in both groups of men. Young and middle-aged men displayed similar body weight and sc abdominal fat accumulation, measured by computed tomography. However, middle-aged men were characterized by a higher percent body fat (28 +/- 5% vs. 22 +/- 7%; P < 0.05) than young subjects. No difference between groups was observed in sc abdominal adipose tissue LPL activity. On the other hand, maximal lipolytic responses of sc abdominal adipocytes to isoproterenol (beta-adrenergic agonist) or to postadrenoceptor agents such as dibutyryl cAMP, forskolin, and theophylline were lower in middle-aged than in young men (P < 0.05). AT-LPL messenger ribonucleic acid (mRNA) levels were similar regardless of the subject's age. However, HSL, C3, and PPAR gamma mRNA levels were higher in middle-aged than in young individuals (P < 0.01-0.05). After correction for percent body fat, only HSL and C3 mRNA levels remained significantly different between groups (P < 0.05). Taken together, these results suggest that aging has an effect on the up-regulation of HSL and C3 mRNA levels, whereas PPAR gamma expression seems to be related mainly to increased adiposity.

Reduced alpha(2)-adrenergic sensitivity of subcutaneous abdominal adipocytes as a modulator of fasting and postprandial triglyceride levels in men.

This study examined the postprandial lipemia of two groups of men displaying similar age, body weight, and regional fat distribution, but characterized by either low (n = 11) or high (n = 15) alpha(2)-adrenergic sensitivity of subcutaneous abdominal adipocytes. In addition to fat cell lipolysis, adipose tissue lipoprotein lipase (AT-LPL) as well as postheparin plasma LPL activities were measured in the fasting state. Fasting AT-LPL and PH-LPL activities were similar in both groups. Maximal adipose cell lipolysis induced by isoproterenol (beta-adrenergic agonist) as well as the beta-adrenergic sensitivity did not differ between both groups of men. The selective alpha(2)-adrenergic agonist UK-14304 promoted a similar antilipolytic response in subcutaneous abdominal adipocytes from both groups. However, the alpha(2)-adrenergic sensitivity, defined as the dose of UK-14304 that produced half-maximal inhibition of lipolysis (IC(50)), was significantly different between groups (P < 0.0001). Men with low versus high subcutaneous abdominal fat cell alpha(2)-adrenergic sensitivity showed higher fasting TG levels. In the whole group, a positive relationship was observed between log-transformed IC(50) UK-14304 values of subcutaneous adipocytes and fasting TG levels (r = 0.39, P < 0.05), suggesting that a low abdominal adipose cell alpha(2)-adrenergic sensitivity is associated with high TG levels. After the consumption of a high-fat meal, subjects with low subcutaneous abdominal adipose cell alpha(2)-adrenergic sensitivity showed higher TG levels in total, medium, and small triglyceride-rich lipoprotein (TRL) fractions at 0- to 6-h time points than men with high adipocyte alpha(2)-adrenergic sensitivity (P values ranging from 0.01 to 0.05). Stepwise regression analysis showed that the fasting TG concentration was the only variable retained as a significant predictor of the area under the curve of TG levels in total TRL fractions (73% of variance) among independent variables such as body weight, percent body fat, visceral and subcutaneous abdominal adipose tissue accumulation measured by CT, as well as subcutaneous abdominal fat cell alpha(2)-adrenoceptor sensitivity. Taken together, these results indicate that a reduced antilipolytic sensitivity of subcutaneous abdominal adipocytes to catecholamines may increase fasting TG levels, which in turn play a role in the etiology of an impaired postprandial TRL clearance in men.

Appetite after weight loss by energy restriction and a low-fat diet-exercise follow-up.

OBJECTIVE: The aim of the present study was to determine the impact of weight loss on appetite as measured by visual analog scale (VAS). METHODS: Seventeen subjects (10 men and seven women) took part in a 15 week weight loss program which consisted of drug therapy (fenfluramine 60 mg/day) or placebo coupled to an energy restriction (-2930 kJ/day; phase 1) followed by an 18 week low-fat diet-exercise follow-up (phase 2). Subjects were given a standardized breakfast before and after phase 1 as well as after phase 2. Individuals were asked to fill out VAS before and at 0, 10, 20, 30, 40, 50 and 60 min after this test meal. Blood samples were drawn before the meal and at 0, 30 and 60 min postprandially and analyzed for glucose and insulin. Fasting plasma cortisol and leptin were also determined. RESULTS: An increase in the fasting desire to eat, hunger and prospective food consumption (PFC) was observed after phase 1 and to an even greater extent after phase 2 in both men and women. In the fasting state, positive correlations were observed between changes in the desire to eat (r=0.76; P<0.05) as well as changes of PFC (r=0. 82; P<0.05) and changes in cortisol at the end of phase 1 for women. In response to phase 1, statistically significant correlations were found between changes of hunger (r=0.64; P<0.05) and desire to eat (r=0.67; P<0.05) as measured by AUC in response to the meal and changes of fasting plasma cortisol in men. The most consistent predictor of changes of baseline desire to eat (r=0.68 P<0.05), fullness (r=-0.78, P<0.05) and PFC (r=0.91, P<0.01) during phase 2 was the change in fasting cortisol in men. Changes of fullness were also associated with changes of fasting leptin in men (r=0.68; P<0. 05) during phase 2. CONCLUSION: These results suggest that weight loss is accompanied by an increase of baseline appetite in both men and women and that the most consistent predictor of these changes in appetite seems to be changes in fasting plasma cortisol.