Brain Remodeling of Appetite Centers in Obesity - Results from Murine Omics Studies and Human Brain Imaging

Tomohiro TanakaJapan Speaker Brain Remodeling of Appetite Centers in Obesity - Results from Murine Omics Studies and Human Brain ImagingBody weight is regulated by functional interplay between multiple organs, among which the hypothalamus plays a critical role through its modulatory functions on energy intake and expenditure. In early 1900s, professors Joseph Babinski and Alfred Frolich reported a case of acquired hypothalamic obesity, whose obesity was secondary to hypothalamic damage by brain tumor. The case provides the first evidence that the hypothalamus plays a key role in the maintenance of body weight in humans. In the 1970s and 1980s, experimental injury or electrical stimulation of the hypothalamic nuclei in rodents further led to an elucidation of its vital role in body weight regulation. Mechanistic insight has been addressed when the discovery of leptin followed by an elucidation of anorexigenic effect of GLP-1 has cast limelight on the endocrinologic aspect of body weight regulation. In fact, more than a dozen genetic forms of obesity has been reported, each of which is caused by mutations of a single gene with indispensable functions within leptin-hypothalamus axis. However, in routine clinical practice, tumors or genetic abnormalities in the hypothalamus are rarely observed in patients with obesity disease. The question, then, is whether the hypothalamus is functioning normally in such patients with primary obesity disease? In 2012, professor Joshua Thaler and colleagues reported that mice fed a high-fat diet exhibit early activation and proliferation of microglia and astrocytes within the hypothalamus - histologic changes suggestive of "hypothalamic inflammation". Subsequent pharmacologic and knockout mouse studies have demonstrated that this hypothalamic inflammation is not merely a result but a critical cause of obesity. We have studied the molecular landscape and its alterations during the development or the improvement of the obesity disease. Methodologically, our research involves transcriptomic and lipidomic analyses of hypothalamic nuclei in mice, with the aim of elucidating the molecular basis of hypothalamic remodeling observed in obese animal models. We have identified obesity-induced biochemical changes in the hypothalamus, such as inflammation-related transcriptome and region-specific accumulation of arachidonic acid esters. More clinically, we are investigating a potential reverse remodeling of the hypothalamus during weight loss in mouse models. Of note, in human subjects with obesity disease, reversible hypothalamic inflammation has been demonstrated using T2 relaxation time measurements in MRI studies. As such, hypothalamic inflammation, a common feature of hypothalamic pathology in rodents and humans, is attracting more attention as a focus of obesity research. In this session, I would like to discuss more of the status quo and future perspectives of the neuropathologic basis of the obesity disease.