The main objective of the Action is to advance our knowledge on the pathogenesis and prevention
of obesity and the specific role of adipose tissue in the development of the metabolic syndrome.
This approach is driven by the hypothesis that adipose tissue is critically involved in transducing
environmental and nutritional factors into endogenous signals which mediate insulin resistance,
vascular complications, beta cell dysfunction and the manifestation of type 2 diabetes.
To reach the overall goal of this project, a multidisciplinary network will address the following
secondary objectives:
1. Analysis of the central regulation of food intake and adipocyte storage function
The main objective of this part of the Action is to identify new molecular targets that may serve to
control food intake and to prevent the development of the metabolic syndrome. One aim is related
to the elucidation of the links between neuroendocrine dysregulation and adipose tissue secretory
function and inflammation. Specifically, different neuroendocrine systems (cortisol axis, sex
hormones, renin-angiotensin system) will be addressed and their impact for the aetiology of the
metabolic syndrome will be evaluated. An additional specific objective is to promote our
knowledge on glucose sensing systems and their role in the control of energy homeostasis and body
weight. This includes attempts to identify hypothalamic genes with specific function for glucose
sensing. A related aim is to study the dysregulation of hypothalamic nutrient sensing focusing on
fatty acids. Furthermore, it is known that hypothalamic systems involved in energy balance and
appetite regulation are subject to profound gender differences. Specific aims are to identify the
molecular basis of this gender-related difference and its impact for obesity and type 2 diabetes.
Adipose cell size is critically related to glucose tolerance and insulin sensitivity. Therefore, a major
goal is to understand how hypertrophy of adipose cells leads to impaired lipid storage capacity,
impaired adipogenesis and systemic insulin resistance.
2. Elucidation of adipose tissue secretory function
Adipose tissue is considered as a major endocrine organ. Advanced knowledge on this endocrine
activity under normal and pathological conditions is of key importance for developing new
strategies to combat major metabolic diseases related to adipose tissue dysfunction. Therefore, the
main objective of this research task is to comprehensively explore the regulation of adipose tissue
secretory function, the origin of secretory products within the tissue, the actions of these products at
the local and peripheral levels and the pathophysiological relevance for humans. Additional
objectives include the identification of novel secretory products and the investigation of the
pathophysiological role of the adipose tissue and its secretory products in human or animal models
of the metabolic syndrome and type 2 diabetes. Additional attempts will be made to define the
secretory activity of different fat depots and their impact for the aetiology of the metabolic
syndrome. Additional aims are to identify variants of genes coding for adipose secretory products,
an important step towards defining new biomarkers of the metabolic syndrome. Finally, attempts
will be made to better understand plasticity of adipose tissue, which may represent a new approach
to prevention of the metabolic syndrome.
3. Assessment of the relationship between cytokines, inflammation and vascular dysfunction
and skeletal muscle insulin resistance
The combined effects of peripheral insulin resistance and vascular disease is devastating as it
promotes uncontrolled hyperglycemia and damaging effects on peripheral organs and beta cells. It
further promotes endothelial cell dysfunction towards the appearance of pre-atherosclerotic lesions
and overt atherosclerosis accompanied with cardiac complications. One main objective is to
identify the downstream targets of the crosstalk between adipose tissue-derived proinflammatory
cytokines and vascular endothelial and smooth muscle cells. This will be essential to develop new
therapeutic strategies for prevention of the secondary complications associated with the metabolic
syndrome and type 2 diabetes. Attempts will also be made to uncover potential synergistic
interactions between cytokines, hyperglycemia and increased levels of free fatty acids. This
knowledge will help to improve therapeutic measures and patient stratification. A second main
objective is to define the molecular targets involved in the initiation of skeletal muscle insulin
resistance. This knowledge is essential for developing novel drug and life-style intervention
strategies.
4. Gluco-lipotoxcity, islet inflammation, beta cell dysfunction and type 2 diabetes
Multifactorial stressful stimuli are harmful to beta cells and affect their survival and function.
Progressive damage and deterioration of these cells lead to decreased beta cell mass, altered insulin
biosynthesis and impaired glucose-regulated insulin secretion. The main objective is to expand the
current research on glucose- and free fatty acid-induced damage to beta cells to the role of adipose
tissue-derived factors (i.e., proinflammatory cytokines) on the function of beta cells in such adverse
environment. Detailed understanding of the molecular mechanisms that lead to beta cell apoptosis
and dysfunction is essential for developing new strategies to prevent or delay the onset of type 2
diabetes. This knowledge will also help to define new biomarkers that may serve to identify patients
at high risk for developing type 2 diabetes. Another important objective is to investigate and
validate a current hypothesis that some harmful proinflammatory cytokines are produced by beta
cells or islets exposed to hyperglycemia or fatty acids. The differentiation between effects of locally
produced cytokines and adipose-tissue derived cytokines may provide better understanding of beta
cell dysfunction and may lead to selective approaches to ameliorate the harmful consequences of
each.
