Abstract
The lateral parabrachial nucleus (lPBN), located in the pons, is a well-recognized anorexigenic center harboring, amongst others, the calcitonin gene-related peptide (CGRP)-expressing neurons that play a key role. The receptor for the orexigenic hormone ghrelin (the growth hormone secretagogue receptor, GHSR) is also abundantly expressed in the lPBN and ghrelin delivery to this site has recently been shown to increase food intake and alter food choice. Here we sought to explore whether GHSR-expressing cells in the lPBN (GHSRlPBN cells) contribute to feeding control, food choice and body weight gain in mice offered an obesogenic diet, involving studies in which GHSRlPBN cells were silenced. We also explored the neurochemical identity of GHSRlPBN cells. To silence GHSRlPBN cells, Ghsr-IRES-Cre male mice were bilaterally injected intra-lPBN with a Cre-dependent viral vector expressing tetanus toxin-light chain. Unlike control wild-type littermates that significantly increased in body weight on the obesogenic diet (i.e., high-fat high-sugar free choice diet comprising chow, lard and 9% sucrose solution), the heterozygous mice with silenced GHSRlPBN cells were resistant to diet-induced weight gain with significantly lower food intake and fat weight. The lean phenotype appeared to result from a decreased food intake compared to controls and caloric efficiency was unaltered. Additionally, silencing the GHSRlPBN cells altered food choice, significantly reducing palatable food consumption. RNAscope and immunohistochemical studies of the lPBN revealed considerable co-expression of GHSR with glutamate and pituitary adenylate cyclase-activating peptide (PACAP), and much less with neurotensin, substance P and CGRP. Thus, the GHSRlPBN cells are important for diet-induced weight gain and adiposity, as well as in the regulation of food intake and food choice. Most GHSRlPBN cells were found to be glutamatergic and the majority (76%) do not belong to the well-characterized anorexigenic CGRP cell population.
Highlights
Calcitonin gene-related peptide (CGRP) neurons in the lateral parabrachial nucleus (lPBN) that project to the central nucleus of the amygdala (CeA) were identified as the profoundly anorexigenic pathway inhibited by agouti-related peptide (AgRP)/neuropeptide Y (NPY)/gamma-aminobutyric acid (GABA) neurons to drive feeding, as revealed by chemogenetic and optogenetic studies in Calca-Cre mice injected with Cre-dependent viral vectors into the lPBN (Carter et al, 2013)
In the present study, using a viral approach that stops cells from signaling, we found that functional silencing of GHSRlPBN cells protected mice from body weight gain and fat accumulation during exposure to an obesogenic HFHS choice diet
Previous studies found global Ghsr-null mice to be resistant to diet-induced obesity when introduced to a high fat diet from an early age (Zigman et al, 2005), an effect that was later reproduced by neuronal ablation of GHSR (Lee et al, 2016) and partly by ablation of GHSR in the arcuate nucleus (ARC) AgRP neurons (Wu et al, 2017)
Summary
The parabrachial nucleus (PBN), located in the pons, is known to relay a broad range of sensory information to forebrain regions (Saper and Loewy, 1980; Fulwiler and Saper, 1984; Bernard et al, 1993; Krout and Loewy, 2000), including information about taste (Norgren and Leonard, 1971; Geran and Travers, 2009; Tokita and Boughter, 2016), as well as aversive information such as visceral malaise (Bernard et al, 1994; Yamamoto et al, 1995; Thiele et al, 1996; Sakai and Yamamoto, 1997) and pain (Gauriau and Bernard, 2002) Part of this neurocircuitry includes an anorexigenic cell group in the lateral parabrachial nucleus (lPBN), that receives GABAergic signaling from the arcuate nucleus (ARC) agouti-related peptide (AgRP)/neuropeptide Y (NPY)/gamma-aminobutyric acid (GABA) neurons, a pathway crucial for feeding to occur (Wu et al, 2009). These findings highlight the key role of lPBN CGRP neurons in the regulation of feeding behaviors
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