measuring-vivo-adipose-tissue-kinetics-humans-using-deuterium-2h

Measuring <em>In Vivo</em> Adipose Tissue Kinetics in Humans Using the Deuterium (<sup>2</sup>H)-Labeling Approach

White adipose tissue is a highly plastic organ that is necessary to maintain whole-body energy homeostasis. The adipose tissue mass and changes in the fat ...

Louisiana State University System

Obesity, characterized by excessive adiposity, is a risk factor for many metabolic pathologies, such as type 2 diabetes mellitus (T2DM). Numerous studies have shown that adipose tissue distribution may be a greater predictor of metabolic health. Upper-body fat (visceral and subcutaneous abdominal) is commonly associated with the unfavorable complications of obesity, while lower-body fat (gluteal-femoral) may be protective. Current research investigations are focused on analyzing the metabolic properties of adipose tissue, in order to better understand the mechanisms that regulate fat distribution in both men and women. This review will highlight the adipose tissue depot- and sex-dependent differences in white adipose tissue function, including adipogenesis, adipose tissue developmental patterning, the storage and release of fatty acids, and secretory function. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

Sex dimorphism and depot differences in adipose tissue function.

To investigate in vitro adipocyte differentiation in baboon fetuses in response to reduced maternal nutrition.

Fetal baboon sex-specific outcomes in adipocyte differentiation at 0.9 gestation in response to moderate maternal nutrient reduction.

The accumulation of fat in upper-body (abdominal) adipose tissue is associated with obesity-related cardiometabolic diseases, whereas lower-body (gluteal and femoral) fat may be protective. Studies suggest physiological and molecular differences between adipose depots and depot-specific cellular mechanisms of adipose expansion. We assessed in vivo cellular kinetics in subcutaneous adipose tissue from the abdominal (scABD) and femoral (scFEM) depots using an 8-week incorporation of deuterium ((2)H) from (2)H2O into the DNA of adipocytes and preadipocytes in 25 women with overweight or obesity. DNA synthesis rates denote new cell formation of preadipocytes and adipocytes in each depot. Formation of adipocytes was positively correlated to that of preadipocytes in the scABD and scFEM depots and was related to percent body fat in each depot. Notably, preadipocytes and adipocytes had higher formation rates in the scFEM depot relative to the scABD. This method to assess in vivo adipogenesis will be valuable to evaluate adipocyte kinetics in individuals with varying body fat distributions and degrees of metabolic health and in response to a variety of interventions, such as diet, exercise, or pharmacological treatment.

Differences in In Vivo Cellular Kinetics in Abdominal and Femoral Subcutaneous Adipose Tissue in Women.

Adipose tissue (AT) expansion occurs by hypertrophy and hyperplasia. Impaired hyperplasia, or adipogenesis, has been associated with obesity-related diseases.

Association of In Vivo Adipose Tissue Cellular Kinetics With Markers of Metabolic Health in Humans.

The storage of lipids in the form of triglycerides (TGs) and the de novo synthesis (lipogenesis) of fatty acids from nonlipid precursors [de novo lipogenesis (DNL)] are important functions of adipose tissue (AT) that influence whole-body metabolism. Yet, few studies have reported in vivo estimates of adipose lipid kinetics in humans. Fifty-two women with obesity (27 African-American and 25 Caucasian; 29.7 ± 5.5 years; BMI 32.2 ± 2.8 kg/m; 44.3 ± 4.0% body fat) were enrolled in the study. In vivo synthesis (or replacement) of TGs (f) as well as the synthesis of the fatty acid, palmitate [a measure of adipose DNL (f)], were assessed using an 8 week incorporation of deuterium into lipids (glycerol and palmitate moieties of TGs) in subcutaneous abdominal (scABD) and subcutaneous femoral (scFEM) AT. We report, for the first time, significant race differences in both TG synthesis and absolute DNL, with Caucasians having higher f and f as compared with African-Americans. The DNL contribution to newly synthesized TG (corrected f) was not different between races. Interestingly, our findings also show that the scFEM adipose depot had higher TG replacement rates relative to the scABD. Finally, the replacement rate of TG (f) was negatively correlated with changes in body weight over the 8 week labeling period. Our results provide the first evidence that in vivo TG replacement (synthesis and breakdown) rates differ by ethnicity. In addition, TG turnover varies by depot location in humans, implying an increased capacity for TG storage and higher lipolytic activity in the scFEM AT.

Racial differences in in vivo adipose lipid kinetics in humans.

White adipose tissue is a highly plastic organ and is an important regulator of whole-body metabolism and energy balance. The magnitude of adipose tissue mass is determined by dynamic changes in the synthesis and breakdown (i.e. turnover) of adipocytes and triacylglycerols (TGs). Obesity is a disorder characterised by excessive adiposity and is a risk factor for diseases, including the metabolic syndrome and type 2 diabetes. Adipose tissue expansion is necessary to accommodate chronic excess energy intake and is characterised by enlargement of existing adipocytes (hypertrophy) and by increase in pre-adipocyte and adipocyte numbers (hyperplasia). Evidence suggests that the manner of subcutaneous adipose expansion can influence metabolic health, as impaired adipogenesis, namely restricted hyperplasia, may lead to ectopic lipid deposition in the liver and skeletal muscle, contributing to the pathogenesis of obesity-related disorders. Despite the plausible role of adipose turnover in human health and pathology, little is known about the in vivo kinetics of adipose tissue components (both adipose cells and TGs). This is due, in part, to the slow turnover rate of adipose tissue and the complexity of directly labelling pathway precursors. This review provides a brief summary of findings derived from in vitro techniques, as well as an overview of two in vivo methods that are being implemented to assess the turnover of adipose cells and TGs. Finally, the role of adipose tissue turnover in metabolic health and disease is discussed.

Dynamics of adipose tissue turnover in human metabolic health and disease.

Cardiotrophin-1 (CT-1) is a gp130 cytokine that was previously characterized for its effects on cardiomyocytes and identified as a marker of heart failure. More recent studies reported elevated circulating levels of CT-1 in humans with obesity and metabolic syndrome (MetS). However, a subsequent rodent study implicated CT-1 as a potential therapeutic target for obesity and MetS. Adipose tissue (AT) is broadly acknowledged as an endocrine organ and is a substantial source of CT-1. However, no study has examined the expression of adipose-derived CT-1 in humans. We present the first analysis of CT-1 mRNA expression in subcutaneous AT and its association with clinical variables in 22 women with obesity and 15 men who were 40% overfed for 8-weeks. We observed that CT-1 expression was higher in the subcutaneous abdominal (scABD) than the femoral (scFEM) depot. Importantly, we reveal that scFEM but not scABD, CT-1 expression was negatively associated with visceral adiposity and intrahepatic lipid, while positively correlated with insulin sensitivity in obese women. Also, men with higher CT-1 levels at baseline had less of a decline in insulin sensitivity in response to overfeeding. Our data provide new knowledge on the regulation of adipose-derived CT-1 in obesity and during weight gain in response to overfeeding in humans and suggest that CT-1 may play a protective role in obesity and related disorders.

The Expression of Adipose Tissue-Derived Cardiotrophin-1 in Humans with Obesity.

African Americans (AAs) have a higher obesity risk than Whites; however, it is unclear if appetite-related hormones and food intake are implicated. We examined differences in appetite-related hormones, appetite, and food intake between AAs ( = 53) and Whites ( = 111) with overweight or obesity. Participants were randomized into a control group or into supervised, controlled exercise groups at 8 kcal/kg of body weight/week (KKW) or 20 KKW. Participants consumed lunch and dinner at baseline and follow-up, with appetite and hormones measured before and after meals (except leptin). At baseline, AAs had lower peptide YY (PYY;  < 0.01) and a blunted elevation in PYY after lunch ( = 0.01), as well as lower ghrelin ( = 0.02) and higher leptin ( < 0.01) compared to Whites. Despite desire to eat being lower and satisfaction being higher in AAs relative to Whites ( ≤ 0.03), no racial differences in food intake were observed. Compared to Whites, leptin increased in the 8 KKW group in AAs ( = 0.01), yet no other race-by-group interactions were evident. Differences in appetite-related hormones between AAs and Whites exist; however, their influence on racial disparities in appetite, food intake, and obesity within this trial was limited.

Racial Variations in Appetite-Related Hormones, Appetite, and Laboratory-Based Energy Intake from the E-MECHANIC Randomized Clinical Trial.

Alcohol (i.e., ethanol) is consumed regularly by much of the adult population; yet, the health effects associated with its use are not well-characterized. Clinical interventions to investigate the effects of moderate alcohol consumption on metabolic outcomes, including adiposity and cardiovascular risk factors, are limited and have yielded conflicting data. In addition, no study has reported the effects of routine alcohol intake during weight loss in a controlled feeding trial. We present the first randomized controlled pilot trial to investigate the effects of moderate alcohol consumption on metabolic outcomes during weight loss in women with obesity. Both groups consumed 30% energy restricted diets and were randomized to either an ethanol-free control (CTL) group or a group (EtOH) that consumed 35 g ethanol daily for eight weeks. Our findings demonstrate that, despite similar weight loss, the decrease in mean arterial pressure was attenuated in the EtOH group, relative to the CTL group ( = 0.02). In addition, decreases in other outcomes, including visceral adipose tissue ( = 0.23), circulating lipids (triglycerides ( = 0.11) and cholesterol ( = 0.11)), and uric acid ( = 0.07) tended to be attenuated with alcohol consumption. These pilot data provide potential evidence that moderate alcohol consumption may mitigate the beneficial effects of weight loss and support the need for larger Randomized Controlled Trials (RCTs) to better investigate the metabolic effects of moderate alcohol intake in humans.

The Effects of Alcohol Consumption on Cardiometabolic Health Outcomes Following Weight Loss in Premenopausal Women with Obesity: A Pilot Randomized Controlled Trial.

In vitro and rodent studies suggest that pioglitazone, a thiazolidinedione, can promote adipogenesis in adipose tissue (AT); however, there is a lack of in vivo studies in humans to support these findings. The objectives of this randomised, placebo-controlled, parallel-arm trial were to test if pioglitazone stimulates in vivo adipogenesis in the subcutaneous adipose tissue depots and if these measures were related to metabolic health outcomes in women with obesity.

Adipose depot-specific effects of 16 weeks of pioglitazone on in vivo adipogenesis in women with obesity: a randomised controlled trial.

Exercise has beneficial effects on metabolism and health. Although the skeletal muscle has been a primary focus, exercise also mediates robust adaptations in white adipose tissue. To determine if exercise affects in vivo adipocyte formation, fifty-two, sixteen-week-old C57BL/6J mice were allowed access to unlocked running wheels [Exercise (EX) group; n = 13 males, n = 13 females] or to locked wheels [Sedentary (SED) group; n = 13 males, n = 13 females] for 4-weeks. In vivo adipocyte formation was assessed by the incorporation of deuterium (2H) into the DNA of newly formed adipocytes in the inguinal and gonadal adipose depots. A two-way ANOVA revealed that exercise significantly decreased new adipocyte formation in the adipose tissue of mice in the EX group relative to the SED group (activity effect; P = 0.02). This reduction was observed in male and female mice (activity effect; P = 0.03). Independent analysis of the depots showed a significant reduction in adipocyte formation in the inguinal (P = 0.05) but not in the gonadal (P = 0.18) of the EX group. We report for the first time that exercise significantly reduced in vivo adipocyte formation in the adipose tissue of EX mice using a physiologic metabolic 2H2O-labeling protocol.

Exercise reduced the formation of new adipocytes in the adipose tissue of mice in vivo.

Adipose tissue (AT) expansion occurs by hypertrophy (increase in size) and hyperplasia (increase in number) of adipocytes. The AT expandability hypothesis postulates that impaired subcutaneous AT expansion leads to ectopic fat accretion, contributing to impaired metabolic health. The role of adipogenesis as a contributing factor is debatable.

A higher proportion of small adipocytes is associated with increased visceral and ectopic lipid accumulation during weight gain in response to overfeeding in men.

Article	Year
Sex dimorphism and depot differences in adipose tissue function. Biochimica et biophysica acta\| PubMed ID: 23684841	2014
Fetal baboon sex-specific outcomes in adipocyte differentiation at 0.9 gestation in response to moderate maternal nutrient reduction. International journal of obesity (2005)\| PubMed ID: 23748190	2014
Differences in In Vivo Cellular Kinetics in Abdominal and Femoral Subcutaneous Adipose Tissue in Women. Diabetes\| PubMed ID: 26993068	2016
Association of In Vivo Adipose Tissue Cellular Kinetics With Markers of Metabolic Health in Humans. The Journal of clinical endocrinology and metabolism\| PubMed ID: 28323935	2017
Racial differences in in vivo adipose lipid kinetics in humans. Journal of lipid research\| PubMed ID: 29910190	2018
Dynamics of adipose tissue turnover in human metabolic health and disease. Diabetologia\| PubMed ID: 30267179	2019
The Expression of Adipose Tissue-Derived Cardiotrophin-1 in Humans with Obesity. Biology\| PubMed ID: 31013924	2019
Racial Variations in Appetite-Related Hormones, Appetite, and Laboratory-Based Energy Intake from the E-MECHANIC Randomized Clinical Trial. Nutrients\| PubMed ID: 31466276	2019
The Effects of Alcohol Consumption on Cardiometabolic Health Outcomes Following Weight Loss in Premenopausal Women with Obesity: A Pilot Randomized Controlled Trial. International journal of environmental research and public health\| PubMed ID: 32717926	2020
Adipose depot-specific effects of 16 weeks of pioglitazone on in vivo adipogenesis in women with obesity: a randomised controlled trial. Diabetologia\| PubMed ID: 33001232	2021
Exercise reduced the formation of new adipocytes in the adipose tissue of mice in vivo. PloS one\| PubMed ID: 33471817	2021
A higher proportion of small adipocytes is associated with increased visceral and ectopic lipid accumulation during weight gain in response to overfeeding in men. International journal of obesity (2005)\| PubMed ID: 35599261	2022

Ursula White

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