Lytle, Kelli A.

Adipose tissue functions as both a storage depot and endocrine organ and is robustly responsive to a nutrient challenge by increasing blood flow. Alterations in adipose tissue blood flow (ATBF) have been described in conditions of metabolic dysfunction. We hypothesized that aging is associated with decreased perfusion to adipose tissue and that normal weight older adults would have decreased basal and glucose challenged ATBF responsiveness and conductance. We recruited 10 (6F/ 4M) generally healthy, non-diabetic, normal weights subjects aged 18-35 years (Younger YO) and 5 (3F/2M) aged 65 to 80 years (Older adults OA). Volunteers had a DEXA scan; the day of the study, volunteers arrived fasted to the clinical research unit and rested for 30 minutes, before starting ATBF measurements using the xenon washout method. ATBF and blood pressures was measured for 30 minutes at rest (baseline) and at 20, 30, and 60 minutes after ingestion of a 75 g glucose drink. We additionally measured fasting and postprandial plasma insulin concentrations (µIU/mL). Compared to the YO, older volunteers had a slightly elevated mean BMI (25.0 ±0.9 vs. 22.4 ±2.1 kg/m 2 , OA vs YO respectively p < 0.05), total body fat (26±7.4 vs. 17±4.6 kg, p < 0.05), upper body fat (8.7±2.8 vs. 5.1±2.1 kg, p < 0.05) and supine resting systolic pressure (136±18.5 107±11.4 mmHg, p < 0.05 ) compared to YO. Although not statistically significant, YO appeared to have a higher median fasting ATBF at baseline (2.8 ± 3.8 vs 1.8±4.3 ml/100g/min, YO vs. OA, respectively) and in response to the glucose challenge at T20 (3.5±2.7 vs 1.7±2.3), T30 (4.2±3.6 vs 1.8±5.2) and T60 (4.2±4.9 vs 1.4±3.9) compared to OA. Because OA appeared to have lower fasting ATBF, we examined whether ATBF responsivity (percent change from baseline) was altered in OA compared to YO. Compared to baseline, YO adults had a +13% at T20, +43% at T30 and +53% at T60. Conversely, OA had a decrease of 31% at T20, and +11% at T30, and +5% at T60. To account for the higher systolic blood pressure in OA we calculated conductance (ATBF/mean arterial pressure (MAP)) at each timepoint. Conductance was not statistically different between YO and OA at baseline, T20, T30 and T60. Interestingly, ATBF was negatively correlated to total upper body fat in both YO (r = 0.74, p< 0.05) and OA (r =0.67, p=.18). OA had higher fasting insulin concentrations than YO and in early response to OGTT at T20 but not at other timepoints. Plasma insulin was not related to either absolute or responsivity of ATBF at any timepoint. In this ongoing study, our preliminary data suggests that during fasting and in response to a 75 gm OGTT challenge, ATBF responsiveness may be altered in older adults. This suggests that reductions in adipose tissue perfusion and responsivity of perfusion in response to a stimulus known to increase adipose tissue blood flow may be impaired in older adults. Even within this normal weight population there was a strong relationship between upper body fat and ATBF. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Adipose tissue (AT) lipolysis insulin resistance results in excess free fatty acid (FFA) release. We tested the hypothesis that the ability of insulin to suppress AT lipolysis is unrelated to the ability of niacin to suppress lipolysis, because niacin acts through a different proximal signaling pathway. Ten volunteers (5 women and 5 men) with upper-body obesity and/or type 2 diabetes mellitus (T2DM) underwent two study visits with overnight intravenous infusions of niacin (1.4 mg/min) or saline, followed by a hyperinsulinemic-euglycemic clamp. FFA-palmitate Ra was measured using [U-13C] and [2H9]palmitate infusions; abdominal AT biopsies were performed before and during the insulin clamp. The suppression of FFA-palmitate Ra by insulin on the saline control day and by niacin after an overnight infusion were highly correlated (r = −0.93, P &lt; 0.001). Fasting AT Akt (pAktS473/474-to-panAkt ratio, P = 0.01) and perilipin 1 (PLN1) (pPLN1S552-to-panPLN1 ratio, P = 0.02) phosphorylation were less during niacin treatment than in the saline control study. Because the suppression of lipolysis by insulin and niacin are highly correlated within individuals and because niacin and insulin act through different proximal signaling pathways, we propose dysregulated AT lipolysis in obesity/T2DM is due to dysfunction(s) in distal lipolysis proteins rather than isolated “insulin resistance.” Article Highlights We undertook this study to compare adipose tissue lipolysis responses to insulin and niacin in humans. We tested the hypothesis that adipose tissue insulin resistance would be unrelated to adipose tissue niacin resistance. The suppression of lipolysis by insulin and niacin were highly correlated. Dysregulated adipose tissue lipolysis in obesity/type 2 diabetes is due to dysfunction(s) in distal lipolysis proteins rather than isolated “insulin resistance.”

Greater degrees of aerobic fitness are associated with greater insulin-mediated muscle glucose uptake. Insulin regulates adipose tissue lipolysis, whether aerobic fitness affects insulin’s ability to regulate lipolysis is unknown. We found that greater fitness is associated with improved adipose tissue insulin responsiveness independent of age, sex, BMI, visceral adipose tissue, body fat (kg), percent body fat, and adipocyte size. This suggests that exercise, if it improves fitness, may improve both adipose tissue and muscle function.

Tryptophan hydroxylase (TPH) is a rate-limiting enzyme for serotonin or 5-hydroxytryptamine (5-HT) synthesis. Previously, adipocyte TPH1 has been linked to increased adipose 5-HT, reduced brown adipose tissue (BAT) thermogenesis, and obesity. However, the role of TPH2, a neural isoform highly expressed in obese adipose tissue, is unknown. Here, we report that adipose tissue expression of TPH2 is dramatically elevated in mice with diet-induced obesity (DIO) and ob/ob mice, as well as in obese humans. In mice fed a high-fat diet, adipocyte TPH2 deficiency improved DIO-induced metabolic complications, enhanced BAT thermogenesis, and increased intestinal energy-harvesting efficiency without affecting adiposity. Conversely, TPH2 overexpression in epididymal adipocytes of chow-fed mice raised adipose and plasma 5-HT levels, suppressed BAT thermogenesis, and exacerbated obesity and metabolic dysfunction. We found that obesity-induced hyperinsulinemia upregulated adipocyte TPH2 expression via activation of mechanistic target of rapamycin complex 1 and SREBP1. In humans, TPH2 mRNA levels in subcutaneous adipose tissue, but not those of TPH1 , are positively correlated with fasting plasma insulin concentrations. In summary, our study demonstrates that obesity-associated increases in adipocyte TPH2 can regulate distal tissue physiology and energy metabolism, suggesting that TPH2 could be a potential therapeutic target for obesity and its associated complications.

Accurate measures of insulin regulation of adipose tissue lipolysis (free fatty acid release rates) in humans can be accomplished using a two-step, hyperinsulinemic clamp experimental design, but careful scrutiny of the data is needed. The FFA palmitate IC 50 measure is reproducible in weight-stable adults and responds to treatment interventions in a quantitative manner.

Background National guidelines recommend that waist circumference (WC) be measured in patients with a body mass index (BMI) 27–35 kg/m2. Unfortunately, perhaps due to logistical reasons, WC is seldom measured in clinical settings. Herein, we describe the performance of a self-operated waist measurement device (SOWMD) as a potential means to overcome barriers to measuring WC. Materials and methods Ten volunteers underwent WC measures by professionals and SOWMD on 5 separate days to assess the reproducibility and accuracy. We then compared SOWMD measures with CT-derived fat content by recruiting 81 patients scheduled for a diagnostic abdominal CT scan. Results There was no difference between professionally measured and SOWMD-measured WC; the intraindividual coefficient of variation over the 5 days was between 0.4% and 2.2%. The WC measured manually, by SOWMD and CT scan were highly correlated (r=0.90–0.92, all p<0.001). The minimal WC measured by SOWMD was a better predictor (r=0.81 for all patients, r=0.87 for men, both p<0.001) of CT-measured visceral adipose tissue volume than other approaches. The minimal WC measured by SOWMD was correlated with fasting plasma glucose (r=0.40, p<0.05), triglyceride (r=0.41, p<0.01) and high-density cholesterol (r=−0.49, p<0.001) concentrations. Conclusion SOWMD is a reproducible, accurate and convenient way to measure WC that can provide added value for health care providers when combined with BMI information.

AbstractWe investigated the relationships between ceramide species concentrations in liver, plasma and very low‐density lipoproteins (VLDL) particles of humans with obesity as well as the relationships between hepatic fat content and hepatic ceramide concentrations and proportional distribution. Twenty‐five obese (body mass index >35 kg/m2) adults participated in this study. Plasma, VLDL and hepatocellular ceramide concentrations were measured by liquid chromatography/tandem mass spectrometry. The proportionate distribution of measured ceramide species differed between liver, whole plasma and the VLDL fraction. We found significant, positive correlations between the proportion of C14:0, C18:0, C20:0 and C24:1 ceramide in the liver and whole plasma (γ = 0.491, p = 0.013; γ = 0.573, p = 0.003; γ = 0.479, p = 0.015; γ = 0.716, p = 0.00006; respectively). In contrast, only the proportional contribution of C24:1 ceramide correlated positively between VLDL and liver (γ = 0.425, p = 0.013). The percent hepatic fat correlated positively with the proportion of C18:1, C18:0 and C20:0 hepatic ceramides (γ = 0.415, p = 0.039; γ = 0.426, p = 0.034; γ = 0.612, p = 0.001; respectively), but not with total hepatic ceramide concentration. The proportions of whole plasma ceramide subspecies, especially C14:0, C18:0, C20:0 and C24:1chain length, are reflective of those of hepatic ceramide subspecies in obese humans; these appear to be markers of hepatic ceramide species composition.

The role of adipose tissue (AT) inflammation in AT function in humans is unclear. We tested whether AT macrophage (ATM) content, cytokine gene expression, and senescent cell burden (markers of AT inflammation) predict AT insulin resistance measured as the insulin concentration that suppresses lipolysis by 50% (IC50). We studied 86 volunteers with normal weight or obesity at baseline and a subgroup of 25 volunteers with obesity before and after weight loss. There was a strong positive relationship between IC50 and abdominal subcutaneous and femoral fat cell size (FCS). The positive, univariate relationships between IC50 and abdominal AT inflammatory markers CD68, CD14, CD206 ATM/100 adipocytes, senescent cells, IL-6, and TNF-α mRNA were not significant after adjustment for FCS. A 10% weight loss significantly reduced IC50; however, there was no reduction in adipose ATM content, senescent cells, or cytokine gene expression. Our study suggests that commonly used markers of AT inflammation are not causally linked to AT insulin resistance, whereas FCS is a strong predictor of AT insulin resistance with respect to lipolysis.

AbstractObjectiveAdipose tissue (AT) senescence is associated with AT dysfunction in rodents, but little is known about human AT senescence. The study goal was to define the distribution of senescent cells in two subcutaneous depots and understand relationships with adiposity and inflammation.MethodsSixty‐three volunteers (48 females) underwent abdominal and femoral subcutaneous fat biopsies. Fat cell size, senescent cells using senescence‐associated β‐galactosidase staining per 100 nucleated cells (percentage), and mRNA expression of four cytokines were measured.ResultsThere was a larger proportion of senescent cells in femoral than abdominal subcutaneous AT (mean difference 1.6% [95% CI: 0.98%‐2.3%], p < 0.001), and the percentage of femoral AT senescent cells was greater in women than men (median 3.9% vs. 2.1%, p < 0.01). There was a positive correlation between senescence and fat cell size in abdominal (rs = 0.44, p < 0.001) and femoral (rs = 0.35, p = 0.007) AT depots. Abdominal AT tumor necrosis factor alpha (rs = 0.49, p < 0.01) and interleukin‐1β (rs = 0.44, p = 0.01) expression was positively correlated with abdominal, but not femoral, AT senescence.ConclusionsIn human subcutaneous AT, there are more senescent cells in femoral than abdominal depots; abdominal AT senescent cells are more associated with inflammatory signals than femoral AT senescent cells.