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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.

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.