Adipose tissue (AT) expansion is accompanied by the infiltration and accumulation of AT macrophages (ATMs), as well as a shift in ATM polarization. Several studies have implicated recruited M1 ATMs in the metabolic consequences of obesity; however, little is known regarding the role of alternatively activated resident M2 ATMs in AT homeostasis or how their function is altered in obesity. Herein, we report the discovery of a population of alternatively activated ATMs with elevated cellular iron content and an iron-recycling gene expression profile. These iron-rich ATMs are referred to as MFehi, and the remaining ATMs are referred to as MFelo. In lean mice, ~25% of the ATMs are MFehi; this percentage decreases in obesity owing to the recruitment of MFelo macrophages. Similar to MFelo cells, MFehi ATMs undergo an inflammatory shift in obesity. In vivo, obesity reduces the iron content of MFehi ATMs and the gene expression of iron importers as well as the iron exporter, ferroportin, suggesting an impaired ability to handle iron. In vitro, exposure of primary peritoneal macrophages to saturated fatty acids also alters iron metabolism gene expression. Finally, the impaired MFehi iron handling coincides with adipocyte iron overload in obese mice. In conclusion, in obesity, iron distribution is altered both at the cellular and tissue levels, with AT playing a predominant role in this change. An increased availability of fatty acids during obesity may contribute to the observed changes in MFehi ATM phenotype and their reduced capacity to handle iron.

The sympathetic nervous system (SNS) plays an essential role in the regulation of metabolic and cardiovascular homeostasis. Low SNS activity has been suggested to be a risk factor for weight gain and obesity development. In contrast, SNS activation is characteristic of a number of metabolic and cardiovascular diseases that occur more frequently in obese individuals. Until recently, the relation between obesity and SNS behavior has been controversial because previous approaches for assessing SNS activity in humans have produced inconsistent findings. Beginning in the early 1990's, many studies using state of the art neurochemical and neurophysiological techniques have provided important insight. The purpose of the present review is to provide an overview of our current understanding of the regional specific alterations in SNS behavior in human obesity. We will discuss findings from our own laboratory which implicate visceral fat as an important depot linking obesity with skeletal muscle SNS activation. The influence of weight change on SNS behavior and the potential mechanisms and consequences of region specific SNS activation in obesity will also be considered.

Obesity is characterized by adipose tissue (AT) macrophage (ATM) accumulation, which promotes AT inflammation and dysfunction. Toll-like receptor 4 (TLR4) deficiency attenuates AT inflammation in obesity but does not impede the accumulation of ATMs. The purpose of the current study was to determine whether TLR4 deficiency alters ATM polarization. TLR4−/− and wild-type mice were fed a low-fat, high-monounsaturated fat (HFMUFA), or a high-saturated fat (HFSFA) diet for 16 weeks. Further, we used a bone marrow transplant model to determine the influence of hematopoietic cell TLR4 signaling. The metabolic and inflammatory responses to high-fat feeding and ATM phenotype were assessed. Global and hematopoietic cell TLR4 deficiency, irrespective of recipient genotype, produced a shift in ATM phenotype toward an alternatively activated state, which was accompanied by reduced AT inflammation. Despite the observed shift in ATM phenotype, neither global nor hematopoietic cell TLR4 deficiency influenced systemic insulin sensitivity after high-fat feeding. Results of the current study suggest that TLR4 directly influences ATM polarization but question the relevance of TLR4 signaling to systemic glucose homeostasis in obesity.

Abstract-We tested the hypothesis that weight loss via a hypocaloric diet would reduce arterial stiffness in overweight and obese middle-aged and older adults. Thirty-six individuals were randomly assigned to a weight loss (nϭ25; age: 61.2Ϯ0.8 years; body mass index: 30.0Ϯ0.6 kg/m 2 ) or a control (nϭ11; age: 66.1Ϯ1.9 years; body mass index: 31.8Ϯ1.4 kg/m 2 ) group. Arterial stiffness was measured via carotid artery ultrasonography combined with applanation tonometry and carotid-femoral pulse wave velocity via applanation tonometry at baseline and after the 12-week intervention. Body weight, body fat, abdominal adiposity, blood pressure, ␤-stiffness index, and carotid-femoral pulse wave velocity were similar in the 2 groups at baseline (all PϾ0.05). Body weight (Ϫ7.1Ϯ0.7 versus Ϫ0.7Ϯ1.1 kg), body fat, and abdominal adiposity decreased in the weight loss group but not in the control group (all PϽ0.05). Brachial systolic and diastolic blood pressures declined (PϽ0.05) only in the weight loss group. Central systolic and pulse pressures did not change significantly in either group. ␤-Stiffness index (Ϫ1.24Ϯ0.22 versus 0.52Ϯ0.37 U) and carotid-femoral pulse wave velocity (Ϫ187Ϯ29 versus 15Ϯ42 cm/s) decreased in the weight loss group but not in the control group (all PϽ0.05). The reductions in carotid-femoral pulse wave velocity were correlated with reductions in total body and abdominal adiposity (rϭ0. all PϽ0.05). However, neither total body nor abdominal adiposity independently predicted reductions in arterial stiffness indices. In summary, our findings indicate that weight loss reduces arterial stiffness in overweight/obese middle-aged and older adults, and the magnitudes of these improvements are related to the loss of total and abdominal adiposity.

Background: Energy intake (EI) regulation is impaired in older adults, but it is not known if habitual physical activity affects accuracy of EI regulation in older compared with young adults. Objective: We hypothesized that the ability to compensate for a high-energy yogurt preload beverage at a subsequent ad libitum meal (i.e. acute compensation) and over the course of the testing day (i.e. short-term compensation) would decrease with age, but the magnitude of the decline would be smaller in physically active compared with sedentary older adults. Design: On two occasions, young active (n ¼ 15), young sedentary (n ¼ 14), older active (n ¼ 14) and older sedentary (n ¼ 11) subjects consumed either a high-energy yogurt preload beverage (YP: 500 ml, 1988 kJ, men; 375 ml, 1507 kJ, women), or no preload (NP), 30 min before an ad libitum test meal. EI at both ad libitum meals was measured, and total daily EI was determined on both testing days. Percent EI compensation for the YP was calculated for the test meal and testing day to determine acute and short-term compensation. Results: Percent EI compensation at the test meal was significantly lower in the older compared with the young subjects (6574 vs 8174%, P ¼ 0.005). There was no effect of habitual physical activity level on acute compensation, and no age by physical activity level interaction (P ¼ 0.60). In contrast, short-term compensation was not different with age (8775 vs 9376%, older vs young, P ¼ 0.45), but was more accurate in active vs sedentary subjects (10075 vs 7976%, P ¼ 0.01). As with acute compensation, there was no age by physical activity interaction (P ¼ 0.39). Conclusion: Acute EI regulation is impaired in older adults, which is not attenuated by physical activity status. However, EI regulation over the course of a day is more accurate in active vs sedentary adults, which may facilitate long-term energy balance. Future work is needed to determine if higher energy expenditure in older active vs older sedentary adults improves long-term EI regulation.

VAN WALLEGHEN, EMILY, JEB S. ORR, CHRIS L. GENTILE, AND BRENDA M. DAVY. Pre-meal water consumption reduces meal energy intake in older but not younger subjects. Obesity. 2007;15:93-99. Objective: To determine whether the consumption of water 30 minutes before an ad libitum meal reduces meal energy intake in young and older adults. Research Methods and Procedures: Healthy, non-obese young (n ϭ 29; age, 21 to 35 years) and older (n ϭ 21; age, 60 to 80 years) individuals were provided with an ad libitum lunch meal on two occasions. Thirty minutes before the lunch meals, subjects were given either a water preload (WP: 375 mL, women; 500 mL, men) or no preload (NP). Energy intake at the two lunch meals was measured. Visual analog scales were used to assess changes in hunger, fullness, and thirst during the meal studies. Results: There was no significant difference in meal energy intake between conditions in the young subjects (892 ϩ 51 vs. 913 Ϯ 54 kcal for NP and WP, respectively; p ϭ 0.65). However, meal energy intake after the WP was significantly reduced relative to the NP condition in the older subjects (682 ϩ 53 vs. 624 Ϯ 56 kcal for NP and WP, respectively; p ϭ 0.02). This effect was caused primarily by the reduction in meal energy intake after water consumption in older men. Hunger ratings were lower and fullness ratings were higher in older compared with younger adults (p Ͻ 0.01). Fullness ratings were higher in the WP condition compared with the NP condition for all subjects (p ϭ 0.01). No age differences in thirst were detected during the test meals. Discussion: Under acute test meal conditions, pre-meal water consumption reduces meal energy intake in older but not younger adults. Because older adults are at increased risk for overweight and obesity, intervention studies are needed to determine whether pre-meal water consumption is an effective long-term weight management strategy for the aging population.

Abstract-We tested the hypothesis that weight gain would increase arterial stiffness in healthy nonobese adults. To address this, we overfed 14 nonobese men (age: 23Ϯ1 years) Ϸ1000 kcal/d for 6 to 8 weeks until a 5-kg weight gain was achieved. Carotid diameters (high-resolution ultrasound) and pressures (applanation tonometry), body composition (dual energy x-ray absorptiometry), and abdominal fat distribution (computed tomography) were measured at baseline and following 4 weeks of weight stability at each individual's elevated body weight. Overfeeding increased body weight 5.1Ϯ0.1 kg and body fat 3.4Ϯ0.4 kg (both PϽ0.001) in 45Ϯ7 days. Total abdominal fat increased 46Ϯ7 cm 2 with weight gain due to increases in both subcutaneous (30Ϯ6 cm 2 ) and visceral fat (15Ϯ4 cm 2 ; all PϽ0.01). As hypothesized, weight gain increased arterial stiffness 13Ϯ6% and decreased arterial compliance 21Ϯ4% (both PϽ0.05). Furthermore, those individuals above the median increase in abdominal visceral fat demonstrated a significantly greater increase in arterial stiffness (0.97Ϯ0.29 versus 0.06Ϯ0.36 U; PϽ0.05) compared with those below the median. Consistent with these observations, the only correlates of the changes in arterial stiffness with weight gain were the increases in total abdominal fat (rϭ0.794), abdominal visceral fat (rϭ0.651), and waist circumference (rϭ0.470; all PϽ0.05). Taken together, these findings suggest that modest weight gain is associated with increases arterial stiffness in nonobese men. The degree of large artery stiffening with weight gain seems to be determined, in part, by the amount of abdominal visceral fat gain. Importantly, this relation is independent of the amount of total body fat gained. Key Words: arterial distensibility Ⅲ adiposity Ⅲ obesity Ⅲ pulse pressure Ⅲ hypertension A pproximately 65% of the US population 1 and Ͼ1 billion people worldwide 2 are overweight or obese and, thus, at increased risk for cardiovascular diseases. 3 There is considerable heterogeneity in the risks associated with excess adiposity; the accumulation of abdominal visceral fat seems to be particularly deleterious. 4,5 Importantly, elevated abdominal visceral fat, independent of total body adiposity, is associated with the development of cardiovascular diseases. 4,5 One mechanism by which the cardiovascular complications associated with obesity may be advanced is through remodeling of the vasculature. The results of numerous studies suggest that obesity is associated with the stiffening of arteries in the cardiothoracic region. 6 -12 Importantly, large artery stiffness is associated with adverse cardiovascular outcomes, 13-16 which occur more frequently in obese individuals. 3,4 The relation between adiposity and arterial stiffness is evident even in young children, 17,18 suggesting that longduration obesity is not a prerequisite for arterial stiffening. Unfortunately, the available data, from observational studies of weight gain, are inconsistent. 19,20 In addition, measurements of body composition were not included in...

We tested the hypothesis that modest, overfeeding-induced weight gain would increase sympathetic neural activity in nonobese humans. Twelve healthy males (23 +/- 2 years; body mass index, 23.8 +/- 0.7) were overfed approximately 1,000 kcal/day until a 5-kg weight gain was achieved. Muscle sympathetic nerve activity (MSNA, microneurography), blood pressure, body composition (dual energy X-ray absorptiometry), and abdominal fat distribution (computed tomography) were measured at baseline and following 4 wk of weight stability at each individual's elevated body weight. Overfeeding increased body weight (73.5 +/- 3.1 vs. 78.4 +/- 3.2 kg, P < 0.001) and body fat (14.9 +/- 1.2 vs. 18 +/- 1.1 kg, P < 0.001) in 42 +/- 8 days. Total abdominal fat increased (220 +/- 22 vs. 266 +/- 22 cm(2), P < 0.001) with weight gain, due to increases in both subcutaneous (158 +/- 15 vs. 187 +/- 12 cm(2), P < 0.001) and visceral fat (63 +/- 8 vs. 79 +/- 12 cm(2), P = 0.004). As hypothesized, weight gain elicited increases in MSNA burst frequency (32 +/- 2 vs. 38 +/- 2 burst/min, P = 0.002) and burst incidence (52 +/- 4 vs. 59 +/- 3 bursts/100 heart beats, P = 0.026). Systolic, but not diastolic blood pressure increased significantly with weight gain. The change in MSNA burst frequency was correlated with the percent increase in body weight (r = 0.59, P = 0.022), change in body fat (r = 0.52, P = 0.043) and percent change in body fat (r = 0.51, P = 0.045). The results of the current study indicate that modest diet-induced weight gain elicits sympathetic neural activation in nonobese males. These findings may have important implications for understanding the link between obesity and hypertension.