Isolation of Adipose Tissue Immune Cells

The discovery of increased macrophage infiltration in  the adipose tissue (AT) of obese rodents and humans has led to an  intensification of interest 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.

Modest weight gain is associated with sympathetic neural activation in nonobese humans.

To determine whether the consumption of water 30 minutes before an ad libitum meal reduces meal energy intake in young and older adults.

Pre-meal water consumption reduces meal energy intake in older but not younger subjects.

The purpose of this investigation was to determine if energy intake compensation is more accurate in males compared to females matched for age, habitual physical activity, cardiorespiratory fitness, and dietary cognitive restraint. Healthy, nonobese young men (n=12) and women (n=12) were provided with an ad libitum lunch meal on two occasions. Thirty minutes prior to the lunch meals, subjects were given either a yogurt preload (YP; 500 mL, 1988 kJ, men; 375 mL, 1507 kJ, women) or no preload (NP). Energy intake at the two lunch meals was measured. Visual analog scales were used to assess changes in hunger and fullness. Blood glucose concentrations were also determined. Energy intake compensation for the YP was significantly more accurate in the male compared to the female subjects (86.2+/-5.0 vs. 73.6+/-4.8% compensation). There were no sex differences in perceptions of hunger and satiety. In the pooled sample, hunger ratings were significantly higher in the NP condition, but there were no significant differences in fullness ratings between test meals. In the YP condition, glycemic response to the preload and the ad libitum meal was significantly higher in males compared to females. These results suggest that under acute test meal conditions, energy intake regulation is more accurate in males. Relative inability to regulate energy intake may predispose females to gain weight over time.

Sex differences in acute energy intake regulation.

We tested the hypothesis that with similar weight gain the increase in blood pressure (BP) would be smaller in men with higher cardiorespiratory fitness (HCRF) than in men with lower cardiorespiratory fitness (LCRF).

Cardiorespiratory fitness influences the blood pressure response to experimental weight gain.

We tested the hypothesis that weight gain would increase arterial stiffness in healthy nonobese adults. To address this, we overfed 14 nonobese men (age: 23+/-1 years) approximately 1000 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 5.1+/-0.1 kg and body fat 3.4+/-0.4 kg (both P<0.001) in 45+/-7 days. Total abdominal fat increased 46+/-7 cm(2) with weight gain due to increases in both subcutaneous (30+/-6 cm(2)) and visceral fat (15+/-4 cm(2); all P<0.01). As hypothesized, weight gain increased arterial stiffness 13+/-6% and decreased arterial compliance 21+/-4% (both P<0.05). Furthermore, those individuals above the median increase in abdominal visceral fat demonstrated a significantly greater increase in arterial stiffness (0.97+/-0.29 versus 0.06+/-0.36 U; P<0.05) 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 (r=0.794), abdominal visceral fat (r=0.651), and waist circumference (r=0.470; all P<0.05). 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.

Large artery stiffening with weight gain in humans: role of visceral fat accumulation.

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 1990s, 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 region 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.

Sympathetic nervous system behavior in human obesity.

We hypothesized that atorvastatin (ATOR) treatment would reduce arterial stiffness in overweight and obese middle-aged and older adults. Twenty-six (11 men and 15 women) overweight or obese (body mass index: 31.6+/-0.7 kg/m(2)) middle-aged and older adults (age: 54+/-2 years) were randomly assigned to receive either ATOR (80 mg/d) or placebo for 12 weeks. Arterial stiffness (beta-stiffness and pulse wave velocity) was measured before and after the intervention. At baseline, the ATOR (n=16) and placebo (n=10) groups did not differ with respect to age, body mass index, blood pressure, serum lipid and lipoprotein concentrations, high-sensitivity C-reactive protein, indices of arterial stiffness, or compliance (all P>0.05). After the 12-week treatment period, the ATOR group experienced a 47% reduction in low-density lipoprotein cholesterol (149+/-6 to 80+/-8 mg/dL) and a 42% reduction in high-sensitivity C-reactive protein (3.6+/-0.8 to 2.1+/-0.5 mg/L; both P<0.05). In addition, beta-stiffness (9.4+/-0.6 to 7.6+/-0.5 U) and aortic pulse wave velocity (1096+/-36 to 932+/-32 cm/s), but not brachial pulse wave velocity, decreased (both P<0.05) with ATOR. In contrast, there were no significant changes in beta-stiffness (9.1+/-0.8 to 9.1+/-0.7 U) or aortic pulse wave velocity (1238+/-89 to 1191+/-90 cm/s; both P>0.05) in the placebo group. There were no relations between the reductions in arterial stiffness indices and any of the baseline cardiometabolic risk factors (all P>0.05). However, the reductions in arterial stiffness were correlated with the reduction in low-density lipoprotein cholesterol but not high-sensitivity C-reactive protein or any other cardiometabolic variables (all P<0.05). Taken together, these findings suggest that ATOR reduces arterial stiffness in overweight and obese middle-aged and older adults, and these favorable changes occur irrespective of baseline cardiometabolic risk factors.

Arterial destiffening with atorvastatin in overweight and obese middle-aged and older adults.

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 (n=25; age: 61.2+/-0.8 years; body mass index: 30.0+/-0.6 kg/m(2)) or a control (n=11; age: 66.1+/-1.9 years; body mass index: 31.8+/-1.4 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, beta-stiffness index, and carotid-femoral pulse wave velocity were similar in the 2 groups at baseline (all P>0.05). Body weight (-7.1+/-0.7 versus -0.7+/-1.1 kg), body fat, and abdominal adiposity decreased in the weight loss group but not in the control group (all P<0.05). Brachial systolic and diastolic blood pressures declined (P<0.05) only in the weight loss group. Central systolic and pulse pressures did not change significantly in either group. beta-Stiffness index (-1.24+/-0.22 versus 0.52+/-0.37 U) and carotid-femoral pulse wave velocity (-187+/-29 versus 15+/-42 cm/s) decreased in the weight loss group but not in the control group (all P<0.05). The reductions in carotid-femoral pulse wave velocity were correlated with reductions in total body and abdominal adiposity (r=0.357-0.602; all P<0.05). 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.

Arterial destiffening with weight loss in overweight and obese middle-aged and older adults.

Mice with CCR2 deficiency are protected from insulin resistance but only after long periods of high-fat diet (HFD) feeding, despite the virtual absence of circulating inflammatory monocytes. We performed a time course study in mice with hematopoietic and global CCR2 deficiency to determine adipose tissue-specific mechanisms for the delayed impact of CCR2 deficiency on insulin resistance.

Aberrant accumulation of undifferentiated myeloid cells in the adipose tissue of CCR2-deficient mice delays improvements in insulin sensitivity.

Macrophage inflammatory protein-1Î± (CCL3) plays a well-known role in infectious and viral diseases; however, its contribution to atherosclerotic lesion formation and lipid metabolism has not been determined. Low density lipoprotein receptor deficient (LDLR(-/-)) mice were transplanted with bone marrow from CCL3(-/-) or C57BL/6 wild type donors. After 6 and 12 weeks on western diet (WD), recipients of CCL3(-/-) marrow demonstrated lower plasma cholesterol and triglyceride concentrations compared to recipients of C57BL/6 marrow. Atherosclerotic lesion area was significantly lower in female CCL3(-/-) recipients after 6 weeks and in male CCL3(-/-) recipients after 12 weeks of WD feeding (P<0.05). Surprisingly, male CCL3(-/-) recipients had a 50% decrease in adipose tissue mass after WD-feeding, and plasma insulin, and leptin levels were also significantly lower. These results were specific to CCL3, as LDLR(-/-) recipients of monocyte chemoattractant protein(-/-) (CCL2) marrow were not protected from the metabolic consequences of high fat feeding. Despite these improvements in LDLR(-/-) recipients of CCL3(-/-) marrow in the bone marrow transplantation (BMT) model, double knockout mice, globally deficient in both proteins, did not have decreased body weight, plasma lipids, or atherosclerosis compared with LDLR(-/-) controls. Finally, there were no differences in myeloid progenitors or leukocyte populations, indicating that changes in body weight and plasma lipids in CCL3(-/-) recipients was not due to differences in hematopoiesis. Taken together, these data implicate a role for CCL3 in lipid metabolism in hyperlipidemic mice following hematopoietic reconstitution.

Impact of macrophage inflammatory protein-1Î± deficiency on atherosclerotic lesion formation, hepatic steatosis, and adipose tissue expansion.

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 (HF(MUFA)), or a high-saturated fat (HF(SFA)) 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.

Article	Year
Modest weight gain is associated with sympathetic neural activation in nonobese humans. American journal of physiology. Regulatory, integrative and comparative physiology\| PubMed ID: 17218435	2007
Pre-meal water consumption reduces meal energy intake in older but not younger subjects. Obesity (Silver Spring, Md.)\| PubMed ID: 17228036	2007
Sex differences in acute energy intake regulation. Appetite\| PubMed ID: 17368641	2007
Cardiorespiratory fitness influences the blood pressure response to experimental weight gain. Obesity (Silver Spring, Md.)\| PubMed ID: 18198309	2007
Large artery stiffening with weight gain in humans: role of visceral fat accumulation. Hypertension\| PubMed ID: 18458161	2008
Sympathetic nervous system behavior in human obesity. Neuroscience and biobehavioral reviews\| PubMed ID: 18602694	2009
Arterial destiffening with atorvastatin in overweight and obese middle-aged and older adults. Hypertension\| PubMed ID: 19687343	2009
Arterial destiffening with weight loss in overweight and obese middle-aged and older adults. Hypertension\| PubMed ID: 20212267	2010
Aberrant accumulation of undifferentiated myeloid cells in the adipose tissue of CCR2-deficient mice delays improvements in insulin sensitivity. Diabetes\| PubMed ID: 21926275	2011
Impact of macrophage inflammatory protein-1Î± deficiency on atherosclerotic lesion formation, hepatic steatosis, and adipose tissue expansion. PloS one\| PubMed ID: 22359597	2012
Toll-like receptor 4 deficiency promotes the alternative activation of adipose tissue macrophages. Diabetes\| PubMed ID: 22751700	2012

Jeb S. Orr

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