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Pro-peptide precursors are processed into biologically active peptide hormones or neurotransmitters, each playing an essential role in physiology and disease. Genetic loss of function of a pro-peptide precursor results in the simultaneous ablation of all biologically-active peptides within that precursor, often leading to a composite phenotype that can be difficult to align with the loss of specific peptide components. Due to this biological constraint and technical limitations, mice carrying the selective ablation of individual peptides encoded by pro-peptide precursor genes, while leaving the other peptides unaffected, have remained largely unaddressed. Here, we developed and characterized a mouse model carrying the selective knockout of the TLQP-21 neuropeptide (ΔTLQP-21) encoded by theVgfgene. To achieve this goal, we used a knowledge-based approach by mutating a codon in theVgfsequence leading to the substitution of the C-terminal Arginine of TLQP-21, which is the pharmacophore as well as an essential cleavage site from its precursor, into Alanine (R21→A). We provide several independent validations of this mouse, including a novel in-gel digestion targeted mass spectrometry identification of the unnatural mutant sequence, exclusive to the mutant mouse. ΔTLQP-21 mice do not manifest gross behavioral and metabolic abnormalities and reproduce well, yet they have a unique metabolic phenotype characterized by a temperature-dependent resistance to diet-induced obesity and activation of the brown adipose tissue.

Vulnerability to stress is given by our genetic make-up and our experiences, therefore it differs between individuals since we are not genetically identical and do not experience the same life events. Moreover, even though stress has been associated obesity, some subjects lose weight instead under stressful conditions. The goal of this thesis is to undercover some of the molecular mechanisms underlying the individual susceptibility to stress which will allow us to better understand how individuals cope better than others. To answer our question we investigated key molecular player involved in adipogenesis, lipolysis, diabetogenesis, sympathetic and insulin signaling markers in metabolically active tissue coming from different strains of mice following exposure to chronic psychosocial stress. Our results showed that a stress induced a complex profile of pro-adipogenic and lipolytic-markers’ expression with a fat depot-specificity as well as strain specificity allowing the contemporary activation of catabolic and anabolic pathways to cope better with stress.