Preproglucagon Neurons in the Nucleus of the Solitary Tract Are the Main Source of Brain GLP-1, Mediate Stress-Induced Hypophagia, and Limit Unusually Large Intakes of Food

Abstract

Centrally administered glucagon-like peptide-1 (GLP-1) supresses food intake. Here we demonstrate that GLP-1-producing (PPG) neurons in the nucleus tractus solitarii (NTS) are the predominant source of endogenous GLP-1 within the brain. Selective ablation of NTS PPG neurons by viral expression of diphtheria toxin subunit A (DTA) substantially reduced active GLP-1 concentrations in brain and spinal cord. Contrary to expectations, this loss of central GLP-1 had no significant effect on ad libitum feeding of mice, affecting neither daily chow intake nor body weight or glucose tolerance. Only after bigger challenges to homeostasis were PPG neurons necessary for food intake control. PPG-ablated mice increased food intake following a prolonged fast and after a liquid diet preload. Consistent with our ablation data, acute inhibition of hM4Di-expressing PPG neurons did not affect ad libitum feeding, however, it increased post-fast refeeding intake and blocked stress-induced hypophagia. Additionally, chemogenetic PPG neuron activation through hM3Dq caused a strong acute anorectic effect. We conclude that PPG neurons are not involved in primary intake regulation, but form part of a secondary satiation/satiety circuit, activated by both psychogenic stress and large meals. Given their hypophagic capacity, PPG neurons might be an attractive drug target in obesity treatment.

Central and peripheral GLP-1 systems independently and additively suppress eating

“…PPG NTS neurons selectively encode large meal satiation PPG NTS neurons are not necessary for control of daily or long term food intake or bodyweight in ad libitum eating mice 7 . However, it is unknown whether they regulate within-or between-meal parameters, or whether the absence of an ablation-induced bodyweight phenotype masks more subtle alterations in energy expenditure or physical activity.…”

Semaglutide lowers body weight in rodents via distributed neural pathways

“…It has been suggested that other regions, such as the ACB, LHA, MTN/PVT, and VTA, could mediate the regulatory effect of GLP-1RAs on food intake (21)(22)(23)(24)(25). Studies suggest a role for brain-derived GLP-1 in the control of eating and reward (80,81), but there is no evidence that peripherally administered GLP-1RAs can directly access GLP-1Rs in these regions, as demonstrated by the lack of fluorescently labeled semaglutide in these brain nuclei. Thus, activation of brain-derived GLP-1 would be necessary for peripherally circulating GLP-1/GLP-1RAs to engage GLP-1Rs in regions such as the ACB or VTA.…”

Glucagon-like Peptide-1 (GLP-1)

“…Preproglucagon (Gcg) is expressed in pancreatic a-cells, in enteroendocrine L-cells throughout the gut, predominantly in the distal ileum and colon, and in a population of neurons in the nucleus tractus solitarii (NTS) of the brainstem [52,84e89]. Diphtheria toxin-induced ablation of preproglucagon-positive neurons in the NTS demonstrated that this small population of neurons is the primary source of endogenous GLP-1 in the brain [90]. Cleavage sites within the proglucagon molecule together with expression of specific prohormone convertase enzymes determines which smaller peptide molecules/hormones are formed, including glicentin (aa 1e69), glicentin-related pancreatic polypeptide (GRPP; aa 1e30), glucagon (aa 33e61), oxyntomodulin (OXM; aa 33e69), the major proglucagon fragment (MPGF; aa 72e158), and the glucagonlike peptides 1 (GLP-1; aa 72e107/108) and 2 (GLP-2; aa 126e 158) ( Figure 1 The expression of Gcg in the pancreas, intestine, and brain is under the control of a single promoter and is initiated from an identical transcription start codon ( Figure 2).…”

“…As discussed above, in addition to enteroendocrine L-cells, GLP-1 is also produced in a discrete set of non-TH-positive neurons in the caudal portions of the NTS [86,148,346e348], and these hindbrain GCG þ positive neurons are the primary source of endogenous brain GLP-1 [90]. Either peripheral administration of leptin [349] or gastric balloon distention [350] acutely activates GLP-1-producing neurons in the NTS, as assessed by cFos immunoreactivity.…”

“…Apart from inducing cFos activity in the same brain areas [696,726,730], LiCl and central GLP-1R agonism both decrease locomotor activity [668,731], slow GI motility and gastric emptying [573,732], reduce body temperature [732,733], and induce adverse gastrointestinal effects including nausea, emesis, and taste avoidance [696,724e726,734e737]. Selective ablation of NTS PPG neurons prevents stress-induced hyperphagia in mice but has no effect on long-term ad libitum food intake, body weight, or glucose tolerance [90]. These data suggest that NTS PPG neurons are not essential for long-term regulation of food intake but are required for the short-term hypophagia in response to stress [738,739].…”