<b><i>Introduction:</i></b> Neuropilin 1 (NRP-1) is a novel co-receptor promoting SARS-CoV-2 infectivity. Animal data indicate a role in trans-endothelial lipid transport and storage. As human data are sparse, we aimed to assess the role of NRP-1 in 2 metabolic active tissues in human obesity and in the context of weight loss-induced short- and long-term metabolic changes. <b><i>Methods:</i></b> After a standardized 12-week weight reduction program, 143 subjects (age &#x3e;18; body mass index ≥27 kg/m², 78% female) were randomized to a 12-month lifestyle intervention or a control group using a stratified randomization scheme. This was followed by 6-month follow-up without any intervention. Phenotyping was performed before and after weight loss, after 12-month intervention and after subsequent 6 months of follow-up. Tissue-specific insulin sensitivity was estimated by HOMA-IR (whole body and mostly driven by liver), insulin sensitivity index (ISI)_Clamp (predominantly skeletal muscle), and free fatty acid (FFA) suppression during hyperinsulinemic-euglycemic clamp (FFA_Supp) (predominantly adipose tissue). NRP-1 mRNA expression was measured in subcutaneous adipose tissue (NRP-1_AT) and skeletal muscle (NRP-1_SM) before and after weight loss. <b><i>Results:</i></b> NRP-1 was highly expressed in adipose tissue (7,893 [7,303–8,536] counts), but neither NRP-1_AT nor NRP-1_SM were related to estimates of obesity. Higher NRP-1_AT was associated with stronger FFA_Supp (<i>r</i> = −0.343, <i>p</i> = 0.003) and a tendency to higher ISI_Clamp (<i>r</i> = 0.202, <i>p</i> = 0.085). Weight loss induced a decline of NRP-1_AT but not NRP-1_SM. This was more pronounced in subjects with stronger reduction of adipose ACE-2 mRNA expression (<i>r</i> = 0.250; <i>p</i> = 0.032) but was not associated with short- and long-term improvement of FFA_Supp and ISI_Clamp. <b><i>Conclusion:</i></b> NRP-1_AT is related to adipose insulin sensitivity in obesity. Weight loss-induced decline of NRP-1_AT seems not to be involved in metabolic short- and long-term improvements after weight loss. However, weight loss-induced reduction of both NRP-1_AT and ACE-2_AT indicates a lower susceptibility of adipose tissue for SARS-CoV-2 after body weight reduction.