Genome editing to reveal peptidergic heterogeneity of POMC neurons regulating energy and glucose balance
Abstract: Diabetes is a
global health concern that has dire consequences if left unchecked. However, the
pathogenesis of diabetes is still not completely understood and so effective treatments
are lacking. Growing evidence has shown that neurons in the brain, particularly those in
the hypothalamus, play an important role in regulating whole body blood glucose, and
that their dysfunctions ... read morecontribute to the development of diabetes. However, the
complexity of the neural system, and difficulties in probing neuronal functions in vivo,
have left us with an incomplete understanding of both the molecular mechanism and
neuro-circuitry of centralized blood glucose regulation. In our recent study, we have
perturbed a major group of glucose-sensing neurons in the hypothalamus,
Pro-opiomelancortin (POMC) neurons in the arcuate nucleus (ARC). We observed that these
groups of neurons play a significant role in regulating whole body glucose homeostasis.
Here we on POMC neurons and utilize a battery of genetic approaches to securitized the
machinery operating within them. Briefly, using a chemogenetic approach with both cell
type and brain region specificity to acutely manipulate the firing of these neurons, we
observed that these neurons directly regulate energy expenditure, locomotion and blood
glucose levels. Utilizing novel CRISPR technology in vivo, we specifically ablated POMC
in the ARC. We found that POMC is necessary for energy and locomotor homeostasis, but
has only a secondary effect on glucose levels. Thus, we hypothesize that another key
neuropeptide found in POMC neurons, cocaine amphetamine regulated transcript (CART) may
control glucose homeostasis. Using a similar approach, we show that CART is necessary to
maintain blood glucose levels and that its depletion in Type 1 diabetes (T1D) and Type 2
diabetes (T2D) mouse models contributes to the development of hyperglycemia. Finally,
using an unbiased approach and terminal inhibition we conclude that the paraventricular
nucleus of the hypothalamus (PVH) is the main downstream glucoregulatory target.
Collectively, these findings provide direct evidence to the underlying molecular
mechanisms of POMC neuronal activity and the neural circuits used to employ them. Our
study has provided novel insight into brain-regulated glucose homeostasis and has
identified potential targets for treating and preventing
Thesis (Ph.D.)--Tufts University, 2018.
Submitted to the Dept. of Cell, Molecular & Developmental Biology.
Advisors: Dong Kong, and Maribel Rios.
Committee: Daniel Jay, Leon Reijmers, and Peng Yi.
Keyword: Neurosciences.read less