High-Fat Diet and Palmitate Alter the Rhythmic Secretion of Glucagon-Like Peptide-1 by the Rodent L-cell

Abstract

Secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1), by the intestinal L-cell is rhythmically regulated by an independent molecular clock. However, the impact of factors known to affect the activity of similar cell-autonomous clocks, such as circulating glucocorticoids and high-fat feeding, on GLP-1 secretory patterns remains to be elucidated. Herein the role of the endogenous corticosterone rhythm on the pattern of GLP-1 and insulin nutrient-induced responses was examined in corticosterone pellet-implanted rats. Moreover, the impact of nutrient excess on the time-dependent secretion of both hormones was assessed in rats fed a high-fat, high-sucrose diet. Finally, the effects of the saturated fatty acid, palmitate, on the L-cell molecular clock and GLP-1 secretion were investigated in vitro using murine GLUTag L-cells. Diurnal variations in GLP-1 and insulin nutrient-induced responses were maintained in animals lacking an endogenous corticosterone rhythm, suggesting that glucocorticoids are not the predominant entrainment factor for L-cell rhythmic activity. In addition to hyperglycemia, hyperinsulinemia, insulin resistance, and disorganization of feeding behavior, high-fat high-sucrose-fed rats showed a total abrogation of the diurnal variation in GLP-1 and insulin nutrient-induced responses, with comparable levels of both hormones at the normal peak (5:00 pm) and trough (5:00 am) of their daily pattern. Finally, palmitate incubation induced profound derangements in the rhythmic expression of circadian oscillators in GLUTag L-cells and severely impaired the secretory activity of these cells. Collectively our findings demonstrate that obesogenic diets disrupt the rhythmic activity of the L-cell, partially through a direct effect of specific nutritional components.

Glucagon‐like peptide‐1: The missing link in the metabolic clock?

“…We have recently shown circadian expression of Bmal1, period‐2 (Per2) and reverse‐erb receptor α in a well‐established in vitro model of the murine (m) intestinal L cell, the murine proglucagon‐SV40 large T antigen (mGLUTag) cell line. Importantly, the pattern in Bmal1 is antiphasic to that of Per2, with periods of ~23–29 h and amplitudes that wane over time as the cells lose synchrony, consistent with findings on Per2 expression in murine β‐cells.…”

“…Considering the variety of therapeutic applications of the peptide, identification of novel GLP‐1 secretagogues is also generating significant interest as an alternative approach to GLP‐1‐based therapy. We have recently shown that the L cell sensitivity to stimuli and the magnitude of the subsequent GLP‐1 responses demonstrate a diurnal pattern in rats and humans that is altered by different types of circadian disruption, such as constant light exposure, feeding at inappropriate times (i.e., during the light period in rodents) and consumption of an obesogenic diet. As these changes are associated with alterations in the patterns of both insulin release and glucose tolerance, these findings provide a link between GLP‐1 secretion and the increased incidence of metabolic syndrome associated with circadian disruption, such as in shift workers.…”

The incretin hormone GLP‐1 and mechanisms underlying its secretion

“…The NCI-H716 cells were isolated from the ascites fluid of a 33-year-old Caucasian male diagnosed with poorly differentiated colon adenocarcinoma 57 and have been reported to secrete GLP-1 in a regulated manner. 32,58 Many factors and signaling pathways regulating GLP-1 secretion have been investigated in this cell line. 48,[59][60][61][62] The heterogeneity of this cell line and its tumor-derived features are certainly limiting factors.…”

Matching Meals to Body Clocks—Impact on Weight and Glucose Metabolism

“…Whether there are circadian rhythms in the release of gut hormones is still poorly described, although GLP-1 has received considerable interest. In a series of in vitro and in vivo experiments, a clear circadian pattern in the release of GLP-1 from rat and human intestinal L cells has been reported [38,39,40]. This pattern is altered by circadian disruptors, including constant light exposure, a Western diet and altered meal patterning (i.e., feeding during the day in rats).…”

“…This response is entrained, since animals that are fed during the day (simulating a night-shift) showed a shift in GLP-1 peak, and a disturbed relationship between GLP-1, insulin and glucose concentrations [39]. In addition, exposure to constant light and feeding a high-fat, high-sucrose ‘Western’ diet, abrogated the normal rhythmic patterns of GLP-1 and insulin release and impaired glucose tolerance [38,39]. …”