Very-low-density lipoprotein triglyceride and free fatty acid plasma kinetics in women with high or low brown adipose tissue volume and overweight/obesity.

Although a high amount of brown adipose tissue (BAT) is associated with low plasma triglyceride concentration, the mechanism responsible for this relationship in people is not clear. Here, we evaluate the interrelationships among BAT, very-low-density lipoprotein triglyceride (VLDL-TG), and free fatty acid (FFA) plasma kinetics during thermoneutrality in women with overweight/obesity who had a low (<20 mL) or high (≥20 mL) volume of cold-activated BAT (assessed by using positron emission tomography in conjunction with 2-deoxy-2-[18F]-fluoro-glucose). We find that plasma TG and FFA concentrations are lower and VLDL-TG and FFA plasma clearance rates are faster in women with high BAT than low BAT volume, whereas VLDL-TG and FFA appearance rates in plasma are not different between the two groups. These findings demonstrate that women with high BAT volume have lower plasma TG and FFA concentrations than women with low BAT volumes because of increased VLDL-TG and FFA clearance rates. This study was registered at ClinicalTrials.gov (NCT02786251).

Chronic Kidney Disease is Associated With Attenuated Plasma Metabolome Response to Oral Glucose Tolerance Testing.

OBJECTIVE: Chronic kidney disease (CKD) is associated with decreased anabolic response to insulin contributing to protein-energy wasting. Targeted metabolic profiling of oral glucose tolerance testing (OGTT) may help identify metabolic pathways contributing to disruptions to insulin response in CKD. METHODS: Using targeted metabolic profiling, we studied the plasma metabolome response in 41 moderate-to-severe nondiabetic CKD patients and 20 healthy controls at fasting and 2 hours after an oral glucose load. We used linear mixed modeling with random intercepts, adjusting for age, gender, race/ethnicity, body weight, and batch to assess heterogeneity in response to OGTT by CKD status. RESULTS: Mean estimated glomerular filtration rate among CKD participants was 38.9 ± 12.7 mL/min per 1.73 m2 compared to 87.2 ± 17.7 mL/min per 1.73 m2 among controls. Glucose ingestion induced an anabolic response resulting in increased glycolysis products and a reduction in a wide range of metabolites including amino acids, tricarboxylic acid cycle intermediates, and purine nucleotides compared to fasting. Participants with CKD demonstrated a blunted anabolic response to OGTT evidenced by significant changes in 13 metabolites compared to controls. The attenuated metabolome response predominant involved mitochondrial energy metabolism, vitamin B family, and purine nucleotides. Compared to controls, CKD participants had elevated lactate:pyruvate (L:P) ratio and decreased guanosine diphosphate:guanosine triphosphate ratio during OGTT. CONCLUSION: Metabolic profiling of OGTT response suggests a broad disruption of mitochondrial energy metabolism in CKD patients. These findings motivate further investigation into the impact of insulin sensitizers and mitochondrial targeted therapeutics on energy metabolism in patients with nondiabetic CKD.

ADRA1A-Gαq signalling potentiates adipocyte thermogenesis through CKB and TNAP.

Noradrenaline (NA) regulates cold-stimulated adipocyte thermogenesis1. Aside from cAMP signalling downstream of ß-adrenergic receptor activation, how NA promotes thermogenic output is still not fully understood. Here, we show that coordinated α1-adrenergic receptor (AR) and ß3-AR signalling induces the expression of thermogenic genes of the futile creatine cycle2,3, and that early B cell factors, oestrogen-related receptors and PGC1α are required for this response in vivo. NA triggers physical and functional coupling between the α1-AR subtype (ADRA1A) and Gαq to promote adipocyte thermogenesis in a manner that is dependent on the effector proteins of the futile creatine cycle, creatine kinase B and tissue-non-specific alkaline phosphatase. Combined Gαq and Gαs signalling selectively in adipocytes promotes a continual rise in whole-body energy expenditure, and creatine kinase B is required for this effect. Thus, the ADRA1A-Gαq-futile creatine cycle axis is a key regulator of facultative and adaptive thermogenesis.

Architecture of the outbred brown fat proteome defines regulators of metabolic physiology.

Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins. We assign co-operative functions to 2,578 proteins, enabling systematic discovery of regulators of BAT. We also identify 638 proteins that correlate with protection from, or sensitivity to, at least one parameter of metabolic disease. We use these findings to uncover SFXN5, LETMD1, and ATP1A2 as modulators of BAT thermogenesis or adiposity, and provide OPABAT as a resource for understanding the conserved mechanisms of BAT regulation over metabolic physiology.

Complex physiology and clinical implications of time-restricted eating.

Time-restricted eating (TRE) is a dietary intervention that limits food consumption to a specific time window each day. The effect of TRE on body weight and physiological functions has been extensively studied in rodent models, which have shown considerable therapeutic effects of TRE and important interactions among time of eating, circadian biology, and metabolic homeostasis. In contrast, it is difficult to make firm conclusions regarding the effect of TRE in people because of the heterogeneity in results, TRE regimens, and study populations. In this review, we 1) provide a background of the history of meal consumption in people and the normal physiology of eating and fasting; 2) discuss the interaction between circadian molecular metabolism and TRE; 3) integrate the results of preclinical and clinical studies that evaluated the effects of TRE on body weight and physiological functions; 4) summarize other time-related dietary interventions that have been studied in people; and 4) identify current gaps in knowledge and provide a framework for future research directions.

Meal Timing and Glycemic Control during Pregnancy-Is There a Link?

Hyperglycemia during pregnancy and gestational diabetes mellitus (GDM) constitute an important public health problem due to their prevalence and long-term health consequences both for the mother and offspring. Results from studies in rodents and some clinical investigations suggest that meal time manipulation may be a potential lifestyle approach against conditions involving perturbations in glucose homeostasis (e.g., hyperglycemia, insulin resistance, diabetes, etc.). The purpose of this review is to summarize and critically evaluate the current literature on the role of meal timing and daily nutrient distribution on glycemic control during pregnancy. Only a small number of mostly observational studies have assessed the role of meal timing in glucose homeostasis during pregnancy. Food consumption earlier in the day and short-term fasting with adequate nutrient intake may improve glycemic control during the second and third trimester of gestation. Considering that the field of chrononutrition is still in its infancy and many questions remain unanswered, future prospective and carefully designed studies are needed to better understand the role of meal timing in metabolic homeostasis and maternal and fetal health outcomes during pregnancy.

Human brown fat, adiposity, and cardiometabolic health: New pieces to the puzzle.

Brown adipose tissue (BAT) is an emerging target against obesity and its related metabolic diseases. Wibmer et al.1 recently reported that human BAT is associated with a healthier fat distribution and improved cardiometabolic health independent of adiposity and fat distribution.

Total-body PET Imaging: A New Frontier for the Assessment of Metabolic Disease and Obesity.

Obesity and associated metabolic syndrome are a global public health issue. Understanding the pathophysiology of this systemic disease is of critical importance for the development of future therapeutic interventions to improve clinical outcomes. The multiorgan nature of the pathophysiology of obesity presents a unique challenge. Total-body PET imaging, either static or dynamic, provides a vital set of tools to study organ crosstalk. The visualization and quantification of tissue metabolic kinetics with total-body PET in health and disease provides essential information to better understand disease physiology and potentially develop diagnostic and therapeutic modalities.

Intermittent fasting as a nutrition approach against obesity and metabolic disease.

PURPOSE OF REVIEW: Intermittent fasting has been proposed as a potential nutrition approach against obesity and metabolic disease. Although data from studies in rodents convincingly support the antiobesity and cardiometabolic benefits of intermittent fasting, its effects in human health are still debatable. RECENT FINDINGS: Recent studies have examined the effect of two intermittent fasting approaches, that is, alternate day fasting (ADF) and time-restricted eating (TRE), on weight loss and cardiometabolic risk factors. ADF seems to be an equally effective weight loss approach to caloric restriction, but adherence to ADF is more challenging. ADF improves cardiometabolic risk factors, whereas it may have superior metabolic benefits compared to caloric restriction in people with insulin resistance. TRE with ad libitum food intake is well tolerated and induces 2-4% weight loss in approximatively 3 months. Additionally, TRE may have metabolic benefits particularly in people with metabolically abnormal obesity even without weight loss. SUMMARY: Intermittent fasting is a promising nutritional approach against obesity and its related metabolic diseases. Further research is needed to: i) establish the long-term effectiveness of TRE in weight loss and metabolic health, ii) improve the long-term adherence to ADF and investigate its weight loss independent effects in metabolic health, and iii) determine the mechanisms underlying the potential cardiometabolic benefits of intermittent fasting in humans.

The role of brown adipose tissue and the thermogenic adipocytes in glucose metabolism: recent advances and open questions.

PURPOSE OF REVIEW: Brown adipose tissue (BAT) and the thermogenic adipocytes in white adipose tissue (WAT) are considered emerging targets against obesity-related metabolic perturbations given their high capacity for thermogenesis and glucose and lipid disposal. This manuscript summarizes and critically evaluates the recent advances on the role of BAT and thermogenic adipocytes in glucose homeostasis in humans. RECENT FINDINGS: Recent studies support that BAT has high capacity for glucose disposal not only during cold but during rewarming and thermoneutrality as well. Moreover, BAT is now considered a metabolic sink for the disposal of branched-chain amino acids improving whole-body glucose metabolism in rodents and, potentially, in humans. ß3 adrenergic agonism and glucagon-like peptide 1 increase BAT metabolic activity for glucose and/or induce the browning of WAT. Finally, recent findings support the association of glucose disposal in BAT with subclinical atherosclerosis and the reproducibility of two advanced medical imaging methods for the assessment of BAT using a glucose radiotracer. SUMMARY: Recent studies provide new insights on the role of human BAT and thermogenic adipocytes in glucose metabolism. However, further research is needed to unequivocally establish the clinical significance of BAT and the thermogenic adipocytes in glucose homeostasis in humans.

Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease.

BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation.

Adipose tissue NAD+ biosynthesis is required for regulating adaptive thermogenesis and whole-body energy homeostasis in mice.

Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme for cellular energy metabolism. The aim of the present study was to determine the importance of brown and white adipose tissue (BAT and WAT) NAD+ metabolism in regulating whole-body thermogenesis and energy metabolism. Accordingly, we generated and analyzed adipocyte-specific nicotinamide phosphoribosyltransferase (Nampt) knockout (ANKO) and brown adipocyte-specific Nampt knockout (BANKO) mice because NAMPT is the rate-limiting NAD+ biosynthetic enzyme. We found ANKO mice, which lack NAMPT in both BAT and WAT, had impaired gene programs involved in thermogenesis and mitochondrial function in BAT and a blunted thermogenic (rectal temperature, BAT temperature, and whole-body oxygen consumption) response to acute cold exposure, prolonged fasting, and administration of ß-adrenergic agonists (norepinephrine and CL-316243). In addition, the absence of NAMPT in WAT markedly reduced adrenergic-mediated lipolytic activity, likely through inactivation of the NAD+-SIRT1-caveolin-1 axis, which limits an important fuel source fatty acid for BAT thermogenesis. These metabolic abnormalities were rescued by treatment with nicotinamide mononucleotide (NMN), which bypasses the block in NAD+ synthesis induced by NAMPT deficiency. Although BANKO mice, which lack NAMPT in BAT only, had BAT cellular alterations similar to the ANKO mice, BANKO mice had normal thermogenic and lipolytic responses. We also found NAMPT expression in supraclavicular adipose tissue (where human BAT is localized) obtained from human subjects increased during cold exposure, suggesting our finding in rodents could apply to people. These results demonstrate that adipose NAMPT-mediated NAD+ biosynthesis is essential for regulating adaptive thermogenesis, lipolysis, and whole-body energy metabolism.

BCAA catabolism in brown fat controls energy homeostasis through SLC25A44.

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health.

Brown and beige fat: From molecules to physiology.

The recent re-discovery of brown adipose tissue (BAT) and even more recent discovery of the browning of white adipose tissue (WAT) in humans have generated intense scientific interest in the role of adipose tissue as potential target against obesity and its metabolic complications. The purpose of this review is to: i) critically evaluate the current evidence on the physiological significance of BAT and the browning of WAT in metabolic function in humans and ii) discuss factors that have been reported to regulate BAT and/or the browning of WAT in humans. The current literature supports that BAT and the browning of WAT constitute promising emerging targets for interventions aiming to prevent and/or treat of obesity and its metabolic complications. Further research is needed to better understand the physiological significance of BAT and browning of WAT in health and disease along with the factors modulating their metabolic function in humans.

Quantification of muscle triglyceride synthesis rate requires an adjustment for total triglyceride content.

Intramyocellular triglyceride (imTG) in skeletal muscle plays a significant role in metabolic health, and an infusion of [13C16]palmitate can be used to quantitate the in vivo fractional synthesis rate (FSR) and absolute synthesis rate (ASR) of imTGs. However, the extramyocellular TG (emTG) pool, unless precisely excised, contaminates the imTG pool, diluting the imTG-bound tracer enrichment and leading to underestimation of FSR. Because of the difficulty of excising the emTGs precisely, it would be advantageous to be able to calculate the imTG synthesis rate without dissecting the emTGs from each sample. Here, we tested the hypothesis that the ASR of total TGs (tTGs), a combination of imTGs and emTGs, calculated as "FSR × tTG pool," reasonably represents the imTG synthesis. Muscle lipid parameters were measured in nine healthy women at 90 and 170 min after the start of [13C16]palmitate infusion. While the measurements of tTG content, enrichment, and FSR did not correlate (P > 0.05), those of the tTG ASR were significantly correlated (r = 0.947, P < 0.05). These results demonstrate that when imTGs and emTGs are pooled, the resulting underestimation of imTG FSR is balanced by the overestimation of the imTG content. We conclude that imTG metabolism is reflected by the measurement of the tTG ASR.

Effect of Progressive Weight Loss on Lactate Metabolism: A Randomized Controlled Trial.

OBJECTIVE: Lactate is an intermediate of glucose metabolism that has been implicated in the pathogenesis of insulin resistance. This study evaluated the relationship between glucose kinetics and plasma lactate concentration ([LAC]) before and after manipulating insulin sensitivity by progressive weight loss. METHODS: Forty people with obesity (BMI = 37.9 ± 4.3 kg/m2 ) were randomized to weight maintenance (n = 14) or weight loss (n = 19). Subjects were studied before and after 6 months of weight maintenance and before and after 5%, 11%, and 16% weight loss. A hyperinsulinemic-euglycemic clamp procedure in conjunction with [6,6-2 H2 ]glucose tracer infusion was used to assess glucose kinetics. RESULTS: At baseline, fasting [LAC] correlated positively with endogenous glucose production rate (r = 0.532; P = 0.001) and negatively with insulin sensitivity, assessed as the insulin-stimulated glucose disposal (r = -0.361; P = 0.04). Progressive (5% through 16%) weight loss caused a progressive decrease in fasting [LAC], and the decrease in fasting [LAC] after 5% weight loss was correlated with the decrease in endogenous glucose production (r = 0.654; P = 0.002) and the increase in insulin sensitivity (r = -0.595; P = 0.007). CONCLUSIONS: This study demonstrates the interrelationships among weight loss, hepatic and muscle glucose kinetics, insulin sensitivity, and [LAC], and it suggests that [LAC] can serve as an additional biomarker of glucose-related insulin resistance.

Non-invasive methods for the assessment of brown adipose tissue in humans.

Brown adipose tissue (BAT) is a recently rediscovered tissue in people that has shown promise as a potential therapeutic target against obesity and its metabolic abnormalities. Reliable non-invasive assessment of BAT volume and activity is critical to allow its importance in metabolic control to be evaluated. Positron emission tomography/computed tomography (PET/CT) in combination with 2-deoxy-2-[18 F]fluoroglucose administration is currently the most frequently used and most established method for the detection and quantification of activated BAT in humans. However, it involves radiation exposure and can detect activated (e.g. after cold exposure), but not quiescent, BAT. Several alternative methods that overcome some of these limitations have been developed including different PET approaches, single-photon emission imaging, CT, magnetic resonance based approaches, contrast-enhanced ultrasound, near infrared spectroscopy, and temperature assessment of fat depots containing brown adipocytes. The purpose of this review is to summarize and critically evaluate the currently available methods that non-invasively probe various aspects of BAT biology in order to assess BAT volume and/or metabolism. Although several of these methods show promise for the non-invasive assessment of BAT volume and function, further research is needed to optimize them to enable an accurate, reproducible and practical means for the assessment of human BAT content and its metabolic function.

An obesity-preventive lifestyle score is negatively associated with pediatric asthma.

PURPOSE: Lifestyle (diet and physical activity) may increase asthma risk, but evidence in this area is lacking. The aims of the present study were to calculate an obesity-preventive lifestyle score comprising of eating and physical activity behaviors and investigate the overall effect of lifestyle on asthma in children. METHODS: A cross-sectional case-control study was carried out in 514 children (217 asthma cases and 297 healthy controls). Data were collected on medical history, anthropometry, dietary intake, and physical activity. We constructed an overweight/obesity-preventive score (OPLS) using study-specific quartile rankings for nine target lifestyle behaviors that were either favorable or unfavorable in preventing obesity (i.e., screen time was an unfavorable lifestyle behavior). The score was developed using the recommendations of the Expert Committee of American Academy of Pediatrics. Score values ranged from 0-18 points; the higher the score, the more protective against high body weight. RESULTS: The OPLS was negatively associated with obesity indices (BMI, waist circumference, and hip circumference), (p < 0.05). Control children had a higher score when compared to asthma cases (9.3 ± 2.7 vs. 8.6 ± 2.9, p = 0.007). A high OPLS was protective against physician-diagnosed asthma (OR 0.92; 95% CI 0.86-0.98, p = 0.014), adjusted for several confounders. The OPLS was no longer protective after adjustment for BMI. CONCLUSION: Higher adherence to an obesity-preventive lifestyle score-consistent with several behaviors for the prevention of childhood overweight/obesity-is negatively associated with obesity indices and lowers the odds for asthma in children. Lifestyle behaviors that contribute to a higher body weight may contribute to the obesity-asthma link. These findings are hypothesis-generating and warrant further investigation in prospective intervention studies.

Brown adipose tissue is associated with systemic concentrations of peptides secreted from the gastrointestinal system and involved in appetite regulation.

OBJECTIVE: Brown adipose tissue (BAT) has been proposed as a potential therapeutic target against obesity and its related metabolic conditions. Data from studies in rodents support a cross talk between BAT and other distal tissues. The relation between BAT and peptide hormones secreted from the gastrointestinal system (GI) and involved in appetite regulation is not known in humans. DESIGN: We studied 18 men during thermoneutral conditions and mild non-shivering cold exposure (CE). METHODS: 2-Deoxy-2-(18F)fluoro-d-glucose positron emission tomography-computed tomography scans were conducted after mild cold to measure BAT volume. Fasting serum concentration of GI-secreted peptides and peptides involved in appetite regulation were measured during thermoneutral conditions and mild CE. RESULTS: During thermoneutral conditions, BAT volume was associated with lower serum concentration of leptin (P = 0.006), gastric inhibitory polypeptide (P = 0.016) and glucagon (P = 0.048) after adjusting for age and body fat percent. CE significantly decreased serum leptin (P = 0.004) and glucagon concentration (P = 0.020), while cold-induced BAT activation was significantly associated with lower serum ghrelin concentration (P = 0.029). CONCLUSIONS: BAT is associated with systemic concentrations of GI-secreted peptides and peptides involved in appetite regulation, suggesting a potential cross talk between BAT and the enteropancreatic axis. Further studies are needed to elucidate the potential link of BAT with the postprandial levels of appetite-regulating peptides and the putative role of BAT in appetite regulation in humans.