Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance

Abstract

Rates of overweight and obesity epidemic have risen significantly in the past few decades, and 34% of adults and 15–20% of children and adolescents in the United States are now obese. Melanocortin receptor 4 (MC4R), contributes to appetite control in hypothalamic neurons and is a promising target for anti‐obesity treatments or drug development. While the presence of functional MC4R is crucial for normal neural control of homeostasis and is altered in obesity and in presence of lipids, the mechanisms underlying altered MC4R trafficking are unknown. Our studies identified a novel C2‐domain protein, C2CD5 that appears to contribute to the regulation of MC4R trafficking. We found that 1) the expression of C2CD5 is decreased in diet‐induced obesity models compared to controls, 2) C2CD5 knock‐out mice exhibit pronounced obesity partially due to an increase in food intake compared to control mice when fed a high‐fat diet, 3) C2CD5 colocalize and interacts with MC4R complex, 4) loss of functional C2CD5 alters MC4R endocytosis, and, 5) C2CD5 knock‐out mice exhibit decreased acute responses to Melanotan‐II injection into the paraventricular hypothalamus. Based on these, we hypothesize that hypothalamic C2CD5 is a MC4R trafficking protein that responds to metabolic cues and is involved in neural control of energy balance. These studies provide evidence for a novel pathway and targets, to develop therapeutic drugs potentially to rescue energy balance defects that contribute to the development and maintenance of obesity. Support or Funding Information This study was supported by AHA SDG and Loyola University Chicago to VMA. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Historic samples reveal loss of wild genotype through domestic chicken introgression during the Anthropocene

“…A total of 112 genes were found to be under selection in the Gallus gallus complex, with a subset of eight solely in domesticated chickens not including selection signals in the outgroups (Figs 3 and S6 and Tables 1 and S5 ). Genes identified as deeply divergent and under selection between domestics and historic wild samples of various subspecies play an important role in such processes as vision maintenance ( CERKL [ 35 ]), reproduction ( CFAP97 [ 36 ], MUS81 [ 37 ]), metabolism ( C2CD5 [ 38 ]), nervous system signaling ( CAPS2 [ 39 ]) and development ( DYNC2H1 [ 40 ], SLTM [ 41 ], GPATCH8 [ 42 ]) ( Fig 3 and Table 1 ). With the exception of CERKL , which emerged as under selection in both wild spadiceus and chickens, the other genes we identified are only under selection in domestic chickens ( Table 1 ).…”

“…Both DYNC2H1 and SLTM code for proteins involved in the Sonic hedgehog pathway that are critical in the formation of organs and the central nervous system during development by regulating neural crest cells [ 53 – 55 ]. We also identified two other genes with relevance to the nervous system– CAPS2 modulates synaptic activities [ 39 ] and C2CD5 regulates body weight and appetite in the hypothalamus [ 38 ]. These properties are not surprising given that tameness is one of the main characteristics being selected for during domestication [ 56 , 57 ].…”

“…Involved in glucose uptake by cells, regulates body weight and appetite control [38] chicken 0.00 0.00…”

Cross-talk between cancer and Pseudomonas aeruginosa mediates tumor suppression

“…Frozen tumors were processed for immunogold transmission electron microscopy in accordance with a published method 82 , 83 with minor modifications. Tumor samples along with their survival data were obtained from patients who had signed informed consent (IRB #H-96-772).…”

Vagal neuron expression of the microbiota-derived metabolite receptor, free fatty acid receptor (FFAR3), is necessary for normal feeding behavior

“…Ambient temperature was maintained at 24.5 °C for all studies using a Phenomaster climate chamber. All experimental groups were BW matched upon the start of metabolic assessment to avoid confounding of BW on energy balance [ 19 ], as described previously [ 20 , 21 ]. Furthermore, ANCOVA with BW as the covariate was used to analyze energy expenditure, as suggested by Tschöp et al.…”