Physiology seminars

Gut-derived signals regulate metabolism, appetite, and behaviors important for mental health. We have performed a large-scale multidimensional screen to identify gut hormones and nutrient-sensing mechanisms in the intestine that regulate metabolism and behavior in the fruit fly Drosophila. We identified several gut hormones that affect fecundity, stress responses, metabolism, feeding, and sleep behaviors, many of which seem to act sex-specifically. We show that in response to nutrient intake, the enteroendocrine cells (EECs) of the adult Drosophila midgut release hormones that act via inter-organ relays to coordinate metabolism and feeding decisions. These findings suggest that crosstalk between the gut and other tissues regulates food choice according to metabolic needs, providing insight into how that intestine processes nutritional inputs and into the gut-derived signals that relay information regulating nutrient-specific hungers to maintain metabolic homeostasis.

Laboratory studies have shown that meaningful changes in light exposure lead to phase shifts in melatonin rhythm. In natural settings, however, light is a very complex signal. How melatonin responds to weekly- and seasonal-dependent variations in light exposure is still poorly understood. In this talk I will present results from a series of observational and intervention studies on the relationship between melatonin and light exposure in the field.

Menstruation is a normal physiological process in women occurring as a result of changes in two ovarian produced hormones – estrogen and progesterone. As a result of these fluctuations, women experience different symptoms in their bodies – their immune system changes (Sekigawa et al, 2004), there are changes in their cardiovascular and digestive system (Millikan, 2006), as well as skin (Hall and Phillips, 2005). But these hormone fluctuations produce major changes in their behavioral pattern as well causing: anxiety, sadness, heightened irritability and anger (Severino and Moline, 1995) which is usually classified as premenstrual syndrome (PMS). In some cases these symptoms severely impair women’s lives and professional help is required. The official diagnosis according to DSM-5 (2013) is premenstrual dysphoric disorder (PMDD). Despite its ubiquitous presence the origins of PMS and PMDD are poorly understood. Some efforts to understand the underlying brain state during the menstruation cycle were performed by using TMS (Smith et al, 1999; 2002; 2003; Inghilleri et al, 2004; Hausmann et al, 2006). But all of these experiments suffer from major shortcomings - no control groups and small number of subjects. Our plan is to address all of these shortcomings and make this the biggest (to our knowledge) experiment of its kind which will, hopefully, provide us with some much needed answers.

All mammals transition from breastfeeding to independent feeding during the lactation period. In humans and other mammals, this critical transition is important for later in life metabolic control and, consequently, for the development of many chronic conditions. Here, Dr. Dietrich will discuss the work of his lab studying the function of hypothalamic neurons involved in homeostatic control during the transition from breastfeeding to independent feeding. His work illuminates novel properties of hypothalamic neurons in early life, suggesting mechanisms by which early life events shape homeostatic regulation throughout the individual’s lifespan.

Sympathetic nerve activation of adrenergic receptors on fat is the major pathway the brain uses to drive non-shivering thermogenesis in brown adipose tissue and lipolysis in white fat. There is accumulating evidence that the peripheral nerve architecture inside of organs is plastic (can be remodeled) but the factors and conditions that regulate or result in remodeling are largely unknown. Particularly for fat, it remains unclear if nerves in fat can be remodeled in step with hyperplasia/trophy of adipose tissue as result of a prolonged energy surfeit. This talk will discuss our recent work identifying the sympathetic nerve architecture in adipose tissue as highly plastic in response to the adipose hormone leptin, the brain circuitry leptin acts on to regulate this and the physiological effects remodeling of innervation has on fat tissue function.

The increasing prevalence of obesity and type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating energy homeostasis to accelerate the identification of new medications. Recent reports indicate that obesity medication, 5-hydroxytryptamine (5-HT, serotonin)2C receptor (5-HT2CR) agonist lorcaserin improves glycemic control in association with weight loss in obese patients with T2D. We examined whether lorcaserin has a direct effect on insulin sensitivity and how this effect is achieved. We clarify that lorcaserin dose-dependently improves glycemic control in a mouse model of T2D without altering body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin’s glucoregulatory effects, via activation of brain pro-opiomelanocortin (POMC) peptides. We observed that lorcaserin reduces hepatic glucose production and improves insulin sensitivity. These data suggest that lorcaserin’s action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease.

This talk will focus on two areas. I will firstly discuss some new data, starting with insights from rare human genetic variants, which helps to clarify the role of the central melanocortin system in the acquisition of nutrients and their disposition into growth, the acquisition of lean mass and sexual maturation . I will then discuss some aspects of the emerging biology of GDF15; a sentinel hormone conveying information regarding a range of somatic stresses to the brain.

Dietary protein quantity and quality greatly impact metabolic health via evolutionary-conserved mechanisms that ensure avoidance of amino acid imbalanced food sources, promote hyperphagia when dietary protein density is low, and conversely produce satiety when dietary protein density is high. Growing evidence support the emerging concept of protein homeostasis in mammals, where protein intake is maintained within a tight range independently of energy intake to reach a target protein intake. The behavioural and neuroendocrine mechanisms underlying these adaptations are unclear and form the focus of our research.