Periodic Reporting for period 1 - CLEARFAT (Sympathetic Wiring of Adipose Tissue)
Período documentado: 2020-06-01 hasta 2022-05-31
Obesity is one of the greatest public health challenges of the 21st century. Whilst obesity itself results in mechanical and psychological problems, the major concern is its association with leptin resistance, type 2 diabetes, fatty liver and a range of other disorders generally known as metabolic syndrome – also including sleep apnoea, musculoskeletal disorders, several types of cancer and cardiovascular disorders including stroke . Metabolic homeostasis is a complex biological process that depends on the overall metabolic rate, balanced between energy expenditure and energy storage. The brain and peripheral tissues are anatomically and functionally connected by the ANS, comprising two antagonistic divisions, the SNS and PNS. The SNS is a multifunctional system which plays an important role in the regulation of several metabolic processes and cardiovascular control.
Neuro-adipose junctions with the sympathetic nervous system (SNS) mediate lipolysis and fat mass reduction6. Thus, direct and targeted activation of SNS inputs to adipose tissues (AT) could represent a new strategy for the induction of fat loss that would circumvent central leptin resistance. While it is known that the autonomic nervous system (ANS) plays a critical role in peripheral lipid metabolism through both its sympathetic and parasympathetic (PNS) branches; however, the mechanisms that underlie the development of the autonomic innervation of AT remain completely unexplored. Even though the functionality of the AT is well described as an endocrine organ with a tight crosstalk within central and peripheral nervous system, the complete architecture of AT also remains elusive, as well as how this may be altered past hyperplasia and hypertrophy in pathological states. The SNS provides a complex homeostatic control to co-ordinate function and crosstalk between white (WAT) and brown adipose tissue (BAT) through dense fibre innervation. Through the actions of the neurotransmitter norepinephrine, SNS modulates important physiological functions of WAT such as lipolysis, adipocyte regeneration and secretion of adipokines. WAT is a biological energy reservoir and a highly active endocrine and metabolic structure in mammals, that in response to over-nutrition expands and in response to energy deficits releases free-fatty acids.
Neuro-adipose junctions with the sympathetic nervous system (SNS) mediate lipolysis and fat mass reduction6. Thus, direct and targeted activation of SNS inputs to adipose tissues (AT) could represent a new strategy for the induction of fat loss that would circumvent central leptin resistance. While it is known that the autonomic nervous system (ANS) plays a critical role in peripheral lipid metabolism through both its sympathetic and parasympathetic (PNS) branches; however, the mechanisms that underlie the development of the autonomic innervation of AT remain completely unexplored. Even though the functionality of the AT is well described as an endocrine organ with a tight crosstalk within central and peripheral nervous system, the complete architecture of AT also remains elusive, as well as how this may be altered past hyperplasia and hypertrophy in pathological states. The SNS provides a complex homeostatic control to co-ordinate function and crosstalk between white (WAT) and brown adipose tissue (BAT) through dense fibre innervation. Through the actions of the neurotransmitter norepinephrine, SNS modulates important physiological functions of WAT such as lipolysis, adipocyte regeneration and secretion of adipokines. WAT is a biological energy reservoir and a highly active endocrine and metabolic structure in mammals, that in response to over-nutrition expands and in response to energy deficits releases free-fatty acids.
The main and general objective of this proposal was to understand the anatomical structure of sympathetic innervation of the adipose tissue and how changes in noradrenaline levels and/or anti-inflammatory pharmacological treatment may modify AT tissue sympathetic innervation.
Both inflammation and innervation of fat depots are of interest in metabolic field as their impairment has been observed the adipose tissue of obese patients. Previous studies have shown a higher number of adipose tissue macrophages in overweight patients, resulting in systemic low-level chronic inflammation. Whether this is a cause of obesity or an effect is still under controversy, but there are evidences that suggest that adipose inflammation play a key role in insulin resistance.
On the other hand, reduction of SNS activity has been identified as a potential risk factor for the development of obesity. More recently, direct synaptic connections between sympathetic neurones and adipocytes have been visualised in white adipose tissue, and stimulation of those neurones induced lipolysis and subsequent weight loss.
From these observations, we hypothesised that a specific non-approved drug for obesity (for confidential interests, here called THM) could combat obesity by reducing the chronic inflammation and increasing the sympathetic activity within adipose tissue. Therefore, we aimed to investigate the effect of THM in diet induce obesity (DIO) mice. Daily THM intraperitoneal administration reduced body weight gain of DIO mice already after 2 weeks of treatment with no differences in food intake. The reduction of body weight is due to a decrease in white adipose tissue content with no affection in lean mass content.
Higher macrophages infiltration in white adipose tissue has been described on obese mice and human, promoting inflammation state of the tissue that contribute to the development of diabetes. THM treatment was able to drastically reduce the amount of macrophages infiltration in DIO mice white adipose tissue, reducing inflammation and thereby this treatment could rescue the obesogenic state induced by high fat diet. Importantly, is notable the results obtained related the sympathetic fibre length. By increasing norepinephrine secretion by sympathetic fibres activated lipolysis that resulted in mice weight loss. Here, we observed that THM treatment increased fibre length and probably the norepinephrine secretion that may modulate the weight loss observed during the treatment .
Altogether, the results demonstrate that changes in sympathetic innervation and/or anti-inflammatory pharmacological treatment may modify AT tissue activity and thereby, modulate the development of obesity.
Exploitation and dissemination of the results has taken place as planned, all the results as well as the new methodology used in the research project was shared with the scientific community through multidisciplinary meetings organised by the host group and International scientific conferences that are important in the field. These data will be also shared through the publication of the results in international peer-review journals with high impact.
Both inflammation and innervation of fat depots are of interest in metabolic field as their impairment has been observed the adipose tissue of obese patients. Previous studies have shown a higher number of adipose tissue macrophages in overweight patients, resulting in systemic low-level chronic inflammation. Whether this is a cause of obesity or an effect is still under controversy, but there are evidences that suggest that adipose inflammation play a key role in insulin resistance.
On the other hand, reduction of SNS activity has been identified as a potential risk factor for the development of obesity. More recently, direct synaptic connections between sympathetic neurones and adipocytes have been visualised in white adipose tissue, and stimulation of those neurones induced lipolysis and subsequent weight loss.
From these observations, we hypothesised that a specific non-approved drug for obesity (for confidential interests, here called THM) could combat obesity by reducing the chronic inflammation and increasing the sympathetic activity within adipose tissue. Therefore, we aimed to investigate the effect of THM in diet induce obesity (DIO) mice. Daily THM intraperitoneal administration reduced body weight gain of DIO mice already after 2 weeks of treatment with no differences in food intake. The reduction of body weight is due to a decrease in white adipose tissue content with no affection in lean mass content.
Higher macrophages infiltration in white adipose tissue has been described on obese mice and human, promoting inflammation state of the tissue that contribute to the development of diabetes. THM treatment was able to drastically reduce the amount of macrophages infiltration in DIO mice white adipose tissue, reducing inflammation and thereby this treatment could rescue the obesogenic state induced by high fat diet. Importantly, is notable the results obtained related the sympathetic fibre length. By increasing norepinephrine secretion by sympathetic fibres activated lipolysis that resulted in mice weight loss. Here, we observed that THM treatment increased fibre length and probably the norepinephrine secretion that may modulate the weight loss observed during the treatment .
Altogether, the results demonstrate that changes in sympathetic innervation and/or anti-inflammatory pharmacological treatment may modify AT tissue activity and thereby, modulate the development of obesity.
Exploitation and dissemination of the results has taken place as planned, all the results as well as the new methodology used in the research project was shared with the scientific community through multidisciplinary meetings organised by the host group and International scientific conferences that are important in the field. These data will be also shared through the publication of the results in international peer-review journals with high impact.
The CLEARFAT project broader our understanding of the control of metabolism by the sympathetic regulation of fat. The understanding of the anatomical structure of sympathetic innervation of the adipose tissue and how changes in noradrenaline levels and/or anti-inflammatory pharmacological treatment may modify AT tissue sympathetic innervation opens a new field in metabolic research.
Direct and targeted activation of sympathetic inputs to adipose tissues represents a new strategy for the induction of fat loss that. We discovered that by specifically targeting sympathetic nervous system energy homeostasis is improved in mice with obesity. The low activity of the SNS related to obese individuals seemed to be a clear cause, and the idea of of using specific drugs that increase sympathetic outflow during obesity seems to be a new target for a worldwide problem.
Direct and targeted activation of sympathetic inputs to adipose tissues represents a new strategy for the induction of fat loss that. We discovered that by specifically targeting sympathetic nervous system energy homeostasis is improved in mice with obesity. The low activity of the SNS related to obese individuals seemed to be a clear cause, and the idea of of using specific drugs that increase sympathetic outflow during obesity seems to be a new target for a worldwide problem.