Neuronal GHS-R Differentially Modulates Feeding Patterns under Normal and Obesogenic Conditions

The orexigenic hormone ghrelin increases food intake and promotes obesity through its receptor, growth hormone secretagogue receptor (GHS-R). We previously reported two neuron-specific GHS-R knockout mouse lines, namely pan-neuronal deletion by Syn1-cre and hypothalamic deletion by AgRP-cre, exhibiting differential diet-dependent effects on body weight. GHS-R deficiency in neurons elicited less pronounced metabolic effects under regular diet (RD) than high fat diet (HFD). While there was no difference in total food intake of HFD in either mouse line, Syn1-cre; Ghsr^f/f mice showed much greater anti-obesity effect than that of AgRP-cre; Ghsr^f/f mice. Meal feeding pattern is known to have a major impact on energy homeostasis and obesity development. Here, we investigated the feeding behaviors of these two neuron-specific GHS-R knockout mice under RD and HFD feeding, by assessing meal number, meal size, meal duration, and feeding frequency. Under the normal diet, RD-fed Syn1-cre; Ghsr^f/f mice showed a decreased meal size in dark phase, while RD-fed AgRP-cre; Ghsr^f/f mice showed an increased meal duration in dark phase. Under the obesogenic diet, HFD-fed Syn1-cre; Ghsr^f/f mice displayed reduced meal numbers in light phase and increased feeding in both light and dark phases, whereas HFD-fed AgRP-cre; Ghsr^f/f mice showed a decreased meal duration in the light phase only. Consistently, the expression of neuropeptides (Neuropeptide Y and Orexin) was increased in the hypothalamus of RD-fed Syn1-cre; Ghsr^f/f mice, whereas the expression of cannabinoid receptor type 1 (CB1) was increased in the hypothalamus of HFD fed Syn1-cre; Ghsr^f/f mice. Overall, feeding pattern changes were more pronounced in Syn1-cre; Ghsr^f/f mice than that in AgRP-cre; Ghsr^f/f mice, and HFD elicited greater alteration than RD. While AgRP-cre; Ghsr^f/f mice consumed HFD meals faster during the day (showing shorter meal duration), Syn1-cre; Ghsr^f/f mice ate few HFD meals during the light phase and ate slowly throughout the day (showing longer meal duration in both phases). Our findings reveal that neuronal GHS-R regulates energy homeostasis by altering feeding patterns, and differentially modulates feeding patterns in a site- and diet-dependent manner. The distinctive data in these two mouse lines also suggest that eating slowly during the optimal feeding period (dark phase for mice) may be beneficial in combating obesity.