A High-Fat Diet Increases Activation of the Glucagon-Like Peptide-1-Producing Neurons in the Nucleus Tractus Solitarii: an Effect that is Partially Reversed by Drugs Normalizing Glycemia

Abstract

Glucagon-like peptide-1 (GLP-1) is a peripheral incretin and centrally active peptide produced in the intestine and nucleus tractus solitarii (NTS), respectively. GLP-1 not only regulates metabolism but also improves cognition and is neuroprotective. While intestinal GLP-1-producing cells have been well characterized, less is known about GLP-1-producing neurons in NTS. We hypothesized that obesity-induced type 2 diabetes (T2D) impairs the function of NTS GLP-1-producing neurons and glycemia normalization counteracts this effect. We used immunohistochemistry/quantitative microscopy to investigate the number, potential atrophy, and activation (cFos-expression based) of NTS GLP-1-producing neurons, in non-diabetic versus obese/T2D mice (after 12 months of high-fat diet). NTS neuroinflammation was also assessed. The same parameters were quantified in obese/T2D mice treated from month 9 to 12 with two unrelated anti-hyperglycemic drugs: the dipeptidyl peptidase-4 inhibitor linagliptin and the sulfonylurea glimepiride. We show no effect of T2D on the number and volume but increased activation of NTS GLP-1-producing neurons. This effect was partially normalized by both anti-diabetic treatments, concurrent with decreased neuroinflammation. Increased activation of NTS GLP-1-producing neurons could represent an aberrant metabolic demand in T2D/obesity, attenuated by glycemia normalization. Whether this effect represents a pathophysiological process preceding GLP-1 signaling impairment in the CNS, remains to be investigated.

The interplay between leptin, glucocorticoids, and GLP1 regulates food intake and feeding behaviour

“…Interestingly, prolonged feeding with a high-fat diet (1 year) leads to increased activation of PPG-NTS neurons in wildtype mice (Lietzau et al, 2022), which is concordant with a lower inhibitory action of leptin in this neural population, likely because of decreased sensitivity to this hormone. Overall, these data support the speculation that obesity is accompanied by a compensatory increase in GLP1 axis activity to promote satiety, but that these mechanisms ultimately fail to prevent excess food intake because of the development of counterbalancing GLP1 and leptin resistance.…”