TEC2022-009

Diabetes and obesity with aging (DOE)

Healthcare technology, precision medicine and aging area

Objectives and lines of research

Humans and rodents, as they age, are characterized by an increase in adiposity probably due, among other factors, to central and peripheral resistance to the actions of insulin and leptin, and by chronic low-grade systemic and local inflammation. These alterations are believed to underlie the age-associated metabolic dysregulation which leads to the development of metabolic diseases such as obesity, type 2 diabetes, hepatic steatosis, and cardiovascular diseases. In fact, several groups, including ours, have proposed that one of the underlying causes of obesity and age-associated metabolic dysfunction is the loss of leptin action, and that the insulin-resistance syndrome is a leptin-resistance syndrome.
In this setting, the laboratory “Diabetes and Obesity with Aging (DOE)” aims to understand the molecular and cellular mechanisms of insulin and leptin resistance associated with aging. This integrative project includes the study in vivo and in vitro of all the main insulin target tissues and the interrelationships between insulin and leptin signaling on glucose and lipid metabolism.
Signaling
In this sense, one aim of our laboratory is to understand how a diminished/deficient central leptin signaling in young leptin sensitive rats is associated to hypothalamic nuclei-specific alterations leading to modifications in eating behavior, locomotor activity and whole-body insulin sensitivity, mimicking the metabolic characteristic of aged rats. We also study whether the central leptin deficiency is associated to hypothalamic nuclei-specific changes in the protein/lipid profile composition by means of mass spectrometry analysis, microglia activation/proliferation and inflammation.

Adipose tissue
We are also interested to understand whether alterations in the plasma membrane lipid composition of visceral adipose tissue in aged rats, which favors an enlarged fat cell size, could constitute a possible survival mechanism preventing that the aged rats from becoming overtly diabetic. Because the hypothalamic-adipose tissue axis is highly related with adiposity and inflammatory disorders, another goal of our research is to investigate whether the central leptin signaling deficiency alters the visceral adipose tissue plasma membrane lipid composition and the sphingolipid metabolism, as well as the local inflammatory response.
Heart
Another goal of our research is to elucidate the precise underling mechanisms by which central leptin, at very low doses, regulates cardiac metabolism and protects against cardiac hypertrophy by regulating PPARs transcription factors. To this end, we study cardiac oxidative and thermogenic capacity, mitochondrial and peroxisomal biogenesis and dynamics as well as functional alterations of proteins from ventricles by means of proteomics technique. This project will contribute to highlight the cellular events involved in the cardioprotective effects of leptin.

Hypothalamic-liver-pancreas axis
The adipokine leptin regulates food intake and peripheral glucose and lipid metabolism through the central melanocortin system and the autonomic nervous system. Hence, we are interested in studying how a diminished/deficient central leptin signaling, which promotes ectopic fat deposition in peripheral tissues, impacts the physiological function of the endocrine pancreas by altering the circulating insulin and glucagon levels. Thus, one aim of our laboratory is to understand the role of the hypothalamic-liver-pancreas axis on the regulation of insulin and glucagon levels mediated by central leptin signaling.