Showing papers by "Harvey J. Grill published in 2020"

A Role for GLP-1 in Treating Hyperphagia and Obesity.

Abstract: Obesity is a chronic recurring disease whose prevalence has almost tripled over the past 40 years. In individuals with obesity, there is significant increased risk of morbidity and mortality, along with decreased quality of life. Increased obesity prevalence results, at least partly, from the increased global food supply that provides ubiquitous access to tasty, energy-dense foods. These hedonic foods and the nonfood cues that through association become reward predictive cues activate brain appetitive control circuits that drive hyperphagia and weight gain by enhancing food-seeking, motivation, and reward. Behavioral therapy (diet and lifestyle modifications) is the recommended initial treatment for obesity, yet it often fails to achieve meaningful weight loss. Furthermore, those who lose weight regain it over time through biological regulation. The need to effectively treat the pathophysiology of obesity thus centers on biologically based approaches such as bariatric surgery and more recently developed drug therapies. This review highlights neurobiological aspects relevant to obesity causation and treatment by emphasizing the common aspects of the feeding-inhibitory effects of multiple signals. We focus on glucagon like peptide-1 receptor (GLP-1R) signaling as a promising obesity treatment target by discussing the activation of intestinal- and brain-derived GLP-1 and GLP-1R expressing central nervous system circuits resulting from normal eating, bariatric surgery, and GLP-1R agonist drug therapy. Given the increased availability of energy-dense foods and frequent encounters with cues that drive hyperphagia, this review also describes how bariatric surgery and GLP-1R agonist therapies influence food reward and the motivational drive to overeat.

NTS and VTA oxytocin reduces food motivation and food seeking.

Abstract: Oxytocin (OT) is a neuropeptide whose central receptor-mediated actions include reducing food intake. One mechanism of its behavioral action is the amplification of the feeding inhibitory effects of gastrointestinal (GI) satiation signals processed by hindbrain neurons. OT treatment also reduces carbohydrate intake in humans and rodents, and correspondingly, deficits in central OT receptor (OT-R) signaling increase sucrose self-administration. This suggests that additional processes contribute to central OT effects on feeding. This study investigated the hypothesis that central OT reduces food intake by decreasing food seeking and food motivation. As central OT-Rs are expressed widely, a related focus was to assess the role of one or more OT-R-expressing nuclei in food motivation and food-seeking behavior. OT was delivered to the lateral ventricle (LV), nucleus tractus solitarius (NTS), or ventral tegmental area (VTA), and a progressive ratio (PR) schedule of operant reinforcement and an operant reinstatement paradigm were used to measure motivated feeding behavior and food-seeking behavior, respectively. OT delivered to the LV, NTS, or VTA reduced 1) motivation to work for food and 2) reinstatement of food-seeking behavior. Results provide a novel and additional interpretation for central OT-driven food intake inhibition to include the reduction of food motivation and food seeking.

Dorsal vagal complex and hypothalamic glia differentially respond to leptin and energy balance dysregulation

Abstract: Previous studies identify a role for hypothalamic glia in energy balance regulation; however, a narrow hypothalamic focus provides an incomplete understanding of how glia throughout the brain respond to and regulate energy homeostasis. We examined the responses of glia in the dorsal vagal complex (DVC) to the adipokine leptin and high fat diet-induced obesity. DVC astrocytes functionally express the leptin receptor; in vivo pharmacological studies suggest that DVC astrocytes partly mediate the anorectic effects of leptin in lean but not diet-induced obese rats. Ex vivo calcium imaging indicated that these changes were related to a lower proportion of leptin-responsive cells in the DVC of obese versus lean animals. Finally, we investigated DVC microglia and astroglia responses to leptin and energy balance dysregulation in vivo: obesity decreased DVC astrogliosis, whereas the absence of leptin signaling in Zucker rats was associated with extensive astrogliosis in the DVC and decreased hypothalamic micro- and astrogliosis. These data uncover a novel functional heterogeneity of astrocytes in different brain nuclei of relevance to leptin signaling and energy balance regulation.

Ghrelin signaling regulates feeding behavior, metabolism, and memory through the vagus nerve

Abstract: Vagal afferent neuron (VAN) signaling sends information from the gut to the brain and is fundamental in the neural control of feeding behavior and metabolism Recent findings reveal that VAN signaling also plays a critical role in cognitive processes, including hippocampus (HPC)-dependent memory VANs, located in nodose ganglia, express receptors for various gut-derived endocrine signals, however, the function of these receptors with regards to feeding behavior, metabolism, and memory control is poorly understood We hypothesized that VAN-mediated processes are influenced by ghrelin, a stomach-derived orexigenic hormone, via communication to its receptor (growth hormone secretagogue receptor [GHSR]) expressed on gut-innervating VANs To examine this hypothesis, rats received nodose ganglia injections of an adeno-associated virus (AAV) expressing short hairpin RNAs targeting GHSR (or a control AAV) for RNA interference-mediated VAN-specific GHSR knockdown Results reveal that VAN GHSR knockdown induced various feeding and metabolic disturbances, including increased meal frequency, impaired glucose tolerance, delayed gastric emptying, and increased body weight compared to controls Additionally, VAN-specific GHSR knockdown impaired HPC-dependent episodic contextual memory and reduced HPC brain-derived neurotrophic factor expression, but did not affect anxiety-like behavior or levels of general activity A functional role for endogenous VAN GHSR signaling was further confirmed by results revealing that VAN signaling is required for the hyperphagic effects of ghrelin administered at dark onset, and that gut-restricted ghrelin-induced increases in VAN firing rate require intact VAN GHSR expression Collective results reveal that VAN GHSR signaling is required for both normal feeding and metabolic function as well as HPC-dependent memory