The WHO defines overweight and obesity as abnormal or excessive fat accumulation that may impair health. Obesity is an extraordinarily complex disease with multifactorial etiology. Many factors may contribute to excess weight gain including genetic, physiological, and environmental factors, combined with eating patterns, physical activity and exercise levels, and sleep routines. The prevalence of obesity continues to dramatically increase worldwide, to the extent of nearly tripled since 1975. As a result, obesity and its metabolic consequences -type II diabetes, cardiovascular diseases, obstructive sleep apnea, gastrointestinal and reproductive disorders, psychological sequelae, or certain types of cancer- have become the main cause of morbidity and mortality in developed countries. What’s more, overweight and obesity are also on the rise in low- and middle-income countries.
Obesity has become a growing health issue in all age groups. The World Health Organization (WHO) estimates that in 2016, around 40% of the adult population was overweight and 19% of children aged 5-19. In 2019, an estimated 38.2 million children under the age of 5 years were overweight or obese. Obesity not only can have a major bearing on life expectancy or impair quality of life, but also has a huge impact on society in terms of healthcare costs linked to the treatment of this pathology and its complications. The WHO European regional obesity report of 2022 estimated that obesity alone was responsible for approximately 8% of health costs in EU Member States in 2014. Although lifestyle changes are the first line of therapy for obesity, these are often insufficient to achieve and maintain the ideal weight over the long term, thus the obesity control guidelines strongly recommend pharmacotherapy along the behavioural interventions, hence the importance of understanding its pathophysiology and the need to search for new therapeutic targets.
The regulation of body weight and fat mass is a complex biological process dependent on the brain's ability to sense, integrate, and send a wide range of signals to generate a behavioral, autonomic, and/or endocrine responses. SIK3 is a protein kinase that belongs to the AMP-activated protein kinase (AMPK) family, which is known as an energy sensor and regulates various aspects of metabolism in both invertebrates and vertebrates. It should be noted that mammalian SIK3 plays an important role in glucose and cholesterol metabolism, among other metabolic functions, at the peripheral level. Also, SIK3 is widely expressed in neurons of the cerebral cortex, thalamus, hypothalamus, and brainstem. This is important since the hypothalamus controls a large number of bodily functions; particularly important among them is the regulation of the energy balance and the endocrine axes. Until now, the role of SIK3 in the central nervous system in relation to energy metabolism was not described, so the main goal of this project was to identify the role of SIK3 in energy balance and its site of action, namely a specific neuronal population. Our results have demonstrated that Sik3 at central level regulates whole-body energy metabolism. Of note, Sik3 fine regulation of metabolism depends on the neuronal type and hypothalamic site of action. We also aimed to studying Sik3 suitability as a target to develop an anti-obesity therapy. Although our results are promising, further research need to be conducted to identify a potential target in this novel pathway to develop an anti-obesity therapy.
