Role of POMC and AgRP neuronal activities on glycaemia in mice

Abstract

Leptin regulates both feeding and glycaemia primarily through its receptors expressed on agouti-related peptide (AgRP) and pro-opiomelanocortin-expressing (POMC) neurons; however, it is unknown whether activity of these neuronal populations mediates the regulation of these processes. To determine this, we injected Cre-dependent designer receptors exclusively activated by designer drugs (DREADD) viruses into the hypothalamus of normoglycaemic and diabetic AgRP-ires-cre and POMC-cre mice to chemogenetically activate or inhibit these neuronal populations. Despite robust changes in food intake, activation or inhibition of AgRP neurons did not affect glycaemia, while activation caused significant (P = 0.014) impairment in insulin sensitivity. Stimulation of AgRP neurons in diabetic mice reversed leptin’s ability to inhibit feeding but did not counter leptin’s ability to lower blood glucose levels. Notably, the inhibition of POMC neurons stimulated feeding while decreasing glucose levels in normoglycaemic mice. The findings suggest that leptin’s effects on feeding by AgRP neurons are mediated by changes in neuronal firing, while the control of glucose balance by these cells is independent of chemogenetic activation or inhibition. The firing-dependent glucose lowering mechanism within POMC neurons is a potential target for the development of novel anti-diabetic medicines.

Optogenetic stimulation of the liver-projecting melanocortinergic pathway promotes hepatic glucose production

“…More surprisingly, mice lacking the Pomc gene exclusively in the hypothalamus show improved glucose tolerance and normal fasting glycemia, while mutant animals develop severe obesity and insulin resistance 5 . Recently, it has been also documented that longterm inhibition of ARC POMC neurons reduces blood glucose levels 17 . These prior findings suggest that the central melanocortin system may have the ability to promote endogenous glucose production.…”

Effects of metabolic state on the regulation of melanocortin circuits

“…These two neuronal populations form neural circuits with various hypothalamic target sites such as the lateral (LHA), and paraventricular (PVH) nucleus as well as with extrahypothalamic nuclei including the bed nucleus of the stria terminalis (BNST), amygdala (AMY), lateral parabrachial nucleus (LPB), periaqueductal grey (PAG), the nucleus of the solitary tract (NTS) and the intermediolateral cell column of the spinal cord (IML) ( Fig. 1 ) [ 8 , 15 , 19 , 30 , 65 , 66 , 93 , 123 , 124 , 128 , 170 , 173 , 182 , 192 ].These neuronal circuit connections are crucial for the proper regulation of feeding behavior, energy homeostasis, and glucose metabolism [ 9 , 19 , 67 , 84 , 115 , 129 , 178 , 187 , 195 ].…”

“…Acute activity of arcuate POMC and NPY/AgRP neurons has been implicated in the regulation of energy expenditure and glucose metabolism [ 43 , 129 , 178 , 187 ]. For example, activation of arcuate AgRP neurons decreases energy expenditure [ 129 ].…”

“…Ablation of arcuate POMC neurons reduces energy expenditure contributing to increased adiposity and metabolic dysfunction [ 211 ]. Moreover, inhibition of POMC neurons stimulates feeding while decreasing glucose levels in normoglycaemic mice [ 187 ]. Together, POMC and NPY/AgRP neurons modify energy balance and glucose homeostasis, however the influence of melanocortin signaling on metabolism might depend on both metabolic state and the activity level in melanocortin circuits.…”

Mitochondrial Dynamics in the Brain Are Associated With Feeding, Glucose Homeostasis, and Whole-Body Metabolism

“…AgRP and POMC neurons of the ARC have opposing effects on glucose metabolism ( 127 ) ( Figure 2Cii ). The mechanisms which allow these two cell types to respond to, and influence, whole body energy status have been elusive.…”