Obesity, which is mainly defined as excess adiposity is an increasing problem globally, however the clinical manifestations of the disease vary between sexes. In most populations, there is a greater prevalence for obesity in women compared to men. However, women tend to retain a healthier phenotype as they gain weight, whereas obese men are at greater risk of developing and dying from obesity-related comorbidities and cardiovascular diseases. On the other hand women with established diabetes are at greater risk from dying from diabetic complications, such as cardiovascular diseases. Women also tend to respond very different from men in diet and weight loss interventions, as previous studies showed that lipolysis in women in higher than men in response to short term fasting. Intermittent fasting has been proposed as a preventive and a therapeutic way to control weight gain in the long-term. Despite its use in the clinical practice, we still do not understand a great part of the molecular components, which mediate the long-term health benefits of intermittent fasting. Most importantly, the sex or gender associated differences of metabolic adaptation to long-term intermittent fasting are understudied. There are fundamental differences in the hormonal profile, adipose tissue distribution, adipose tissue innervation, vascularization and immune response between females and males. However, accumulating evidence from studies in humans and mice point to sex hormone independent differences in adipocyte metabolism and particularly adipocyte mitochondrial energetics, which can affect systemic energy expenditure levels and glucose homeostasis. Our research is focusing on sex associated differences of white and brown adipose tissue mitochondrial function adaptation to fasting and intermittent fasting diet patterns in male and female mice and humans.
Sex-associated differences in mitochondrial function adaptation to intermittent fasting
We will challenge male and female mice with obesogenic diets, such as a HFD and diet patterns that contribute to long-term weight control, such as every other day fasting (intermittent fasting). We will work with mouse models with endogenously labelled mitochondria (MitoTag mouse) and we will focus on description on adipose tissue mitochondrial networks, mitochondrial dynamics and biochemistry, utilizing imaging and mitochondrial multi omics analysis (transcriptomics, proteomics and metabolomics). Already existing collaborations will allow the investigation of key finding in human tissues from men and women. Due to the already described important differences of the immune response on metabolism between sexes, we will also clarify the role of adipose tissue immune cells on the observed sex dimporphic phenotypes. The immunological aspects of the project will be done in close collaboration with Alberta Diabetes Institute (ADI).
Mitochondria are key organelles in adipose tissue insulin sensitivity, energetics and in systemic metabolic health. Recent evidence support the existence of small proteins, i.e < 100aa, deriving from mitochondria, also called mitochondria derived peptides (MDPs). MDPs are bioactive peptides that are encoded either from small open reading frames (sORFs) or they are generated from proteolysis of bigger mitochondrial localized proteins. Several bioactive MDPs have been shown to be secreted from cells and they have been quantified in the serum of humans, such as humanin and MOTS-c. The field of MDPs is new and very few peptides have been described so far, with hundreds pending to be mapped and linked to metabolism. Our research is focusing on the identification and study of MDPs in the context of obesity and adipose tissue energy expenditure, as well as their sex dimorphism aspects.
Adipose tissue mitochondrial derived peptides in obesity and energy expenditure
We will work with mouse models of genetic obesity, diet induced obesity and cold exposure / cold mimicking models, as well as in vitro culturing of white and brown adipocytes from mouse and human. We will follow a combination of transcription-based (in collaboration with Alberta Diabetes Institute (ADI)), peptide mapping and computational approaches to identify MDPs from white and brown adipose tissue. Candidate peptides will be synthesized and tested for their effects on adipocytes´ mitochondrial function and adipocyte metabolism. Upon identification of bioactive MDPs, we will follow up their potential therapeutic metabolic benefits in mice and investigate their target pathways in adipocytes.