Periodic Reporting for period 2 - ObeSIK3 (Role of SIK3 in energy homeostasis)
Reporting period: 2023-04-16 to 2024-04-15
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.
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.
The general objective of this proposal was to identify a new brain regulatory pathway (mediated by Sik3) in the maintenance of energy balance. To achieve this, we use genetic tools to identify the brain area and neuronal population where Sik3 could be acting as an energy sensor. First, we generate mutant mouse lines using the Cre-lox technology. In this method, Sik3 exon 13 is deleted (gain of function mutant) in the cells expressing Cre recombinase. We employed 9 different Cre mice lines covering a wide range of brain areas. Two of the mice lines evaluated provided us with exciting results, suggesting a role of Sik3 in the brain regulating energy homeostasis. Second, to narrow down the brain area responsible for the obese phenotype we inoculated adeno-associated virus with cre recombinase on Sik3 floxed mice in specific brain nuclei. We could observe different regulatory patterns by Sik3, depending on the brain region. The study of the specific components of energy balance was performed by growth curves, respiratory and metabolic analysis by mass spectrometry using the ARCO system, and characterization of glucose homeostasis and insulin resistance by glucose tolerance test (GTT) and insulin tolerance test (ITT). Third, it was planned to identify the possible downstream effectors mediating Sik3 regulation of energy balance. Although no clear target was detected a possible role of Sik3 in neuronal dynamics was analyzed by fiber photometry studies. We disseminated the results in 3 international congresses, as well as to the general public in 2 public events and 1 visit to a school.
Obesity and its metabolic consequences have become major causes of morbidity and mortality in developed countries. For this reason, much effort is being placed on identifying the basic molecular mechanisms controlling energy balance. ObeSIK3 represented a novel approach to describe the role of CNS’ Sik3 in energy metabolism, unraveling a new regulatory pathway for the maintenance of energy and glucose homeostasis, these being of importance due to the demand for advanced knowledge to develop new anti-obesity and diabetes therapeutics in the future. All the experiments were conducted to detect possible gender differences as both men and women could be the end-users of the potential drug treatment derived from this research. The relevance of our project is that we have uncover the role of Sik3 in the brain in the regulation of energy balance. In this regard, two neuronal types where identify where Sik3 oppositely regulates whole-body metabolism, likely by altering neuronal dynamics in a feeding-dependent manner. This is of importance and should be taken into consideration for the design of new therapeutics targeting this novel pathway, to avoid unwanted side effects or ineffectiveness of the potential drug.