The constant increase in the obese and overweight population creates opportunities for novel therapeutic innovations to allow people to eat without getting fat and getting sick. Here, fed a hyperlipidic diet (HD)C57BL6 thimet oligopeptidase null (THOP1-/-) male mice were shown to gain only 25% (females gained 60%) of the weight gained by control wild type (WT) mice. Distinct from WT mice,THOP1-/- fed HD exhibited normal blood glucose levels and no insulin resistance. THOP1-/-fed HD phenotype benefits also include regular blood cholesterol levels, reduced fat in adipose and liver tissues, increased adipose tissue adrenergic-stimulated lipolysis, and greater resistance and endurance on treadmill running tests at high intensity. THOP1-/-compared to WT have alterations on the expression levels of specific genes and microRNAs related to obesity. Intracellular peptides that had their relative levels altered in THOP1-/-were shown to modulate the expression levels of genes and mature microRNAs associated to obesity, in 3T3L1 adipocyte. The ubiquitous existence of intracellular peptides in different cells of different species suggests a broader biological significance of the present results, connecting proteasomal protein degradation to protein synthesis. These exciting results suggest THOP1 and intracellular peptides as novel therapeutic targets to control obesity and obesity-associated diseases.