Endocrine Abstracts

The hypothalamus plays a central role in the neuroendocrine regulation of energy homeostasis and appetite. Congenital or acquired disruption of hypothalamic nuclei disrupts the balance between energy intake and expenditure is leading to rapid and excessive weight gain. Hypothalamic obesity (HO) is further complicated by disturbances in the hypothalamic-pituitary axis, sleep disruption, visual impairment, and neurological and vascular sequelae. Among suprasellar tumours, craniopharyngioma is the most common cause of acquired hypothalamic obesity, either directly or secondary to surgical or radiotherapeutic interventions. Current strategies for managing HO include optimising pituitary hormone replacement, restricting calorie intake, increasing physical activity, behavioural interventions, pharmacotherapy, and bariatric surgery. Pharmacotherapeutic approaches involve stimulants that increase energy consumption, agents that reduce sympathomimetic activity, anti-diabetic agents and direct modification of cerebral satiety signalling through stimulation of cocaine-amphetamine regulated transcript. Pharmacological studies of HO report weight loss or stabilisation but reported intervention periods are short, and others report no effect. More recently, GLP1 receptor agonists (GLP1RA) have shown improved outcomes in the treatment of HO, potentially related to GLP1RA action on extra-hypothalamic brain centres. Other therapies currently being trailed include Methionine Aminopeptidase Inhibitors therapy decreasing lipogenesis, increasing fat oxidation, and increasing lipolysis, and Tesomet (tesofensine and metoprolol). New agents targeting pro-opiomelanocortin (POMC), MC4 receptors and AgRP/NPY neurons, in the hypothalamus may offer better outcomes. The challenge in achieving weight loss, modification in eating behaviour and improvement in energy expenditure in acquired HO reflects the complexity of hypothalamic control of energy homeostasis and feeding. Defining the location of hypothalamic damage may support the development of targeted therapies. There is a need for novel or combined approaches to achieve significant and sustained weight loss in HO. Placebo-controlled trials using current single or combination therapies are thus necessary to determine the efficacy of these treatments.