An Integrated Understanding of the Molecular Mechanisms of How Adipose Tissue Metabolism Affects Long-term Body Weight Maintenance

Mai, Knut; Li, Linna; Wiegand, Susanna; Brachs, Maria; Leupelt, Verena; Ernert, Andrea; Kühnen, Peter; Hübner, Norbert; Robinson, Peter N.; Chen, Wei; Krude, Heiko; Spranger, Joachim

doi:10.2337/db18-0440

Cited by 23 publications

(33 citation statements)

References 39 publications

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“…Pre-trial weight loss phase: A structured weight reduction program (caloric restriction using a very low energy diet and nutritional counseling, physical exercises and psychological advices) was used to achieve a weight loss of at least 8%. The detailed protocol was already reported previously [ 18 ] and is given in the supplement.…”

Section: Methodsmentioning

confidence: 99%

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Metabolic impact of weight loss induced reduction of adipose ACE-2 – Potential implication in COVID-19 infections?

Spranger

Soll

et al. 2020

Metabolism

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Background & aims Angiotensin converting enzyme (ACE)-2 is a modulator of adipose tissue metabolism. However, human data of adipose ACE-2 is rarely available. Considering that, ACE-2 is believed to be the receptor responsible for cell entry of SARS-CoV-2, a better understanding of its regulation is desirable. We therefore characterized the modulation of subcutaneous adipose ACE-2 mRNA expression during weight loss and the impact of ACE-2 expression on weight loss induced short- and long-term improvements of glucose metabolism. Methods 143 subjects (age > 18; BMI ≥ 27 kg/m 2 ) were analyzed before and after a standardized 12-week dietary weight reduction program. Afterwards subjects were randomized to a 12-month lifestyle intervention or a control group (Maintain-Adults trial). Insulin sensitivity (IS) was estimated by HOMA-IR (as an estimate of liver IS) and ISI Clamp (as an estimate of skeletal muscle IS). ACE-2 mRNA expression (ACE-2 AT ) was measured in subcutaneous adipose tissue before and after weight loss. Results ACE-2 AT was not affected by obesity, but was reduced in insulin resistant subjects. Weight loss resulted in a decline of ACE-2 AT (29.0 (20.0–47.9) vs. 21.0 (13.0–31.0); p = 1.6 ∗ 10 −7 ). A smaller reduction of ACE-2 AT (ΔACE-2 AT ) was associated with a larger improvement of ISI Clamp ( p = 0.013) during weight reduction over 3 months, but not with the extend of weight loss. The degree of changes in insulin resistance were preserved until month 12 and was also predicted by the weight loss induced degree of ΔACE-2 AT ( p = 0.011). Conclusions Our data indicate that subcutaneous adipose ACE-2 expression correlates with insulin sensitivity. Weight loss induced decline of subcutaneous adipose ACE-2 expression might affect short- and long-term improvement of myocellular insulin sensitivity, which might be also relevant in the context of ACE-2 downregulation by SARS-CoV-2. Trial registration: ClinicalTrials.gov number: NCT00850629 , https://clinicaltrials.gov/ct2/show/NCT00850629 , date of registration: February 25, 2009.

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Section: Methodsmentioning

confidence: 99%

“…This multimodal lifestyle intervention was comparable to sessions of the weight loss period. Details of the protocol and the intervention were already reported [ 16 , 18 ] and are described in the supplement.…”

Section: Methodsmentioning

confidence: 99%

Metabolic impact of weight loss induced reduction of adipose ACE-2 – Potential implication in COVID-19 infections?

Spranger

Soll

et al. 2020

Metabolism

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“…All subjects gave written informed consent (21,22). Briefly, obese subjects were anthropometrically and metabolically phenotyped (oGTT, calorimetry, bioimpedance, HE clamps) and subcutaneous WAT (scWAT)/SKM biopsy samples were taken before (T-3) and after (T0) 3 months of WR through lifestyle intervention and analyzed by RNA sequencing to discover differentially expressed genes (23).…”

Section: Clinical Studymentioning

confidence: 99%

“…To explore the role of NNMT and its metabolites in humans and to check which findings from the mouse are transferrable, we analyzed data from a human WR study (23). Study participants were extensively characterized before (T-3) and after (T0) a 3-month WR intervention study.…”

Section: Nnmt and Its Metabolites In A Human Wr Studymentioning

confidence: 99%

Genetic Nicotinamide N-Methyltransferase (Nnmt) Deficiency in Male Mice Improves Insulin Sensitivity in Diet-Induced Obesity but Does Not Affect Glucose Tolerance

et al. 2018

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Antisense oligonucleotide knockdown (ASO-KD) of nicotinamide N-methyltransferase (NNMT) in high-fat diet (HFD)–fed mice has been reported to reduce weight gain and plasma insulin levels and to improve glucose tolerance. Using NNMT-ASO-KD or NNMT knockout mice (NNMT−/−), we tested the hypothesis that Nnmt deletion protects against diet-induced obesity and its metabolic consequences in males and females on obesity-inducing diets. We also examined samples from a human weight reduction (WR) study for adipose NNMT (aNNMT) expression and plasma 1-methylnicotinamide (MNAM) levels. In Western diet (WD)–fed female mice, NNMT-ASO-KD reduced body weight, fat mass, and insulin level and improved glucose tolerance. Although NNMT−/− mice fed a standard diet had no obvious phenotype, NNMT−/− males fed an HFD showed strongly improved insulin sensitivity (IS). Furthermore, NNMT−/− females fed a WD showed reduced weight gain, less fat, and lower insulin levels. However, no improved glucose tolerance was observed in NNMT−/− mice. Although NNMT expression in human fat biopsy samples increased during WR, corresponding plasma MNAM levels significantly declined, suggesting that other mechanisms besides aNNMT expression modulate circulating MNAM levels during WR. In summary, upon NNMT deletion or knockdown in males and females fed different obesity-inducing diets, we observed sex- and diet-specific differences in body composition, weight, and glucose tolerance and estimates of IS.

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“…In contrast, it seems that only a substantial and sustained weight loss is effective to prevent cardiovascular disease [4]. Current evidence indicates that the frequently observed body weight regain might be mediated by the persistence of regain promoting hormonal and neuronal adaptions [5], [6], [7], [8]. Numerous neuroimaging studies aimed to identify factors determining successful body weight regulation.…”

Section: Introductionmentioning

confidence: 99%

Interaction of circulating GLP-1 and the response of the dorsolateral prefrontal cortex to food-cues predicts body weight development

Maurer

Mai

Krude

et al. 2019

Molecular Metabolism

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ObjectivesThis study evaluated the impact of the interaction between the anorexigenic incretin hormone glucagon-like peptide-1 (GLP-1) and reward-related brain activity in the dorsolateral prefrontal cortex (DLPFC), a key area of behavioral control, on future weight loss in obese individuals.MethodsWe performed a weight loss-weight maintenance intervention study over 27 months. We applied an fMRI food-cue reactivity paradigm during which the participants were passively exposed to food pictures to evaluate neuronal activity in the DLPFC. Additionally, we measured concentrations of circulating GLP-1 levels during a standard oral glucose tolerance test. Phenotyping was performed consecutively before and after a 3-month low-calorie diet as well as after a randomized 12-month trial, investigating the effect of a combined behavioral intervention on body weight maintenance. Participants were then followed-up for another 12 months without further intervention.ResultsUsing voxel-wise linear mixed-effects regression analyses, we evaluated 56 measurements and identified a strong interaction between circulating, endogenous GLP-1 levels and DLPFC activity predicting body weight change over the total observation period (t = −6.17, p = 1.6 · 10−7). While neither the GLP-1 nor the DLPFC response individually predicted the subsequent weight change, participants achieved body weight loss when the GLP-1 and the DLPFC responses occurred concurrently.ConclusionsOur data demonstrate an interaction between a peripheral hormonal signal and central nervous activity as robust predictor of body weight change throughout the different periods of a long-term life-style intervention. The preeminent role of their interdependency compared to the partly ambivalent effects of the single components argues for integrative approaches to improve sensitivity and reliability of weight prediction conventionally based on individual biomarkers.

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An Integrated Understanding of the Molecular Mechanisms of How Adipose Tissue Metabolism Affects Long-term Body Weight Maintenance

Abstract: Clinical trial reg. no. NCT00850629, clinicaltrials.gov This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/

Cited by 23 publications

References 39 publications

Metabolic impact of weight loss induced reduction of adipose ACE-2 – Potential implication in COVID-19 infections?

Metabolic impact of weight loss induced reduction of adipose ACE-2 – Potential implication in COVID-19 infections?

Genetic Nicotinamide N-Methyltransferase (Nnmt) Deficiency in Male Mice Improves Insulin Sensitivity in Diet-Induced Obesity but Does Not Affect Glucose Tolerance

Interaction of circulating GLP-1 and the response of the dorsolateral prefrontal cortex to food-cues predicts body weight development

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