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Orexin

Post BPD-DS orexin levels offer insights into metabolism and biomarkers

The orexin changes occurred as early as one day post-op
There was a significant continued reduction of fasting cholesterol, triglyceride and LDL-cholesterol

An acute post-bariatric surgery increase in orexin levels is associated with rapid improvement in glucose metabolism, according to a study published online in the journal PlosOne.

The study researchers from the Centre de Recherche Institut Universitaire de Cardiologie & Pneumologie de Québec, Université Laval, Québec, Canada, and the Department of Physiology, King George’s Medical University, Lucknow, India, said that this post-operative increase in orexin levels is associated with the maintenance of increased orexin throughout the one-year follow-up period, adding that the study provides valuable information on potential biomarkers for targeting in therapy.

There are a number of peptide hormones such as apelin, orexin, ghrelin and leptin that play a role in obesity pathophysiology, associated metabolic alterations and energy balance.

Orexin (or hypocretin) is a neurotransmitter that regulates arousal, wakefulness, and appetite. It is known to increase the craving for food and correlates with the function of the substances that promote its production.

Orexin-producing cells have been shown to be inhibited by leptin (through the leptin receptor pathway), but are activated by ghrelin and hypoglycemia (glucose inhibits Orexin production). Orexin is a very important link between metabolism and sleep regulation.

Orexin levels have also been shown to increase during low energy conditions and decrease when energy levels are high, therefore soaring Orexin levels trigger wakefulness, vigilance and hunger. In addition to promoting wakefulness and regulating food intake, orexin-A has been implicated in diabetes mellitus and obesity.

As a result, the researchers investigated the short- and long-term (up to one year) changes in plasma orexin levels and the association with metabolic changes following biliopancreatic diversion with duodenal switch (BPD-DS) bariatric surgery.

Study

Results for orexin levels for all 76 subjects over the one year time indicate a significant change overall (Figure 1). However, when subjects were evaluated individually, there was a range in orexin response: orexin increased (Orexin-INC) in some subjects, in other subjects orexin remained unchanged and in other subjects, orexin decreased (Orexin-DEC).

Figure 1. Plasma orexin levels (ng/ml) pre-operative (baseline; BSL) and post-operative at one and five days (D), six and 12 months (M) following BPD-DS bariatric surgery.

The orexin changes occurred as early as one day post-op, and remained consistent within each subject, such that the % change at one day correlated closely with % change at five days (r=0.526, p<0.0001), six months (r=0.410, p=0.0006) and 12 months (r=0.410, p=0.0006). Baseline plasma Orexin levels were not significantly different between the two groups (3.31±0.31 vs. 2.92±0.28ng/mL).

Within the first few days following the surgery (up to five days), there was no significant change in body composition between Orexin-INC and Orexin-DEC groups. However, at six months, there were marked decreases in BMI in both groups by 25–27%, reflecting a decrease in both fat mass (22–24%) and lean mass, but with comparable changes in both groups. This was also true at 12 months, with further decreases in BMI (36% to 37%) and percent body fat (average 36%) although the patient weight status still remained within the obese range.

Out of 33 Orexin-DEC subjects, 15 (45%) were diabetic compared with 11 (55%) patients in the Orexin-INC group. Post-operatively, there was a marked reduction in the diabetic status, but there was no difference between groups. However, although changes in weight and % fat mass were comparable between both groups, the response to various glucose and lipid parameters was not the same.

In the Orexin-DEC group at baseline, 15 (45%) were being treated with lipid lowering therapy, while 10 (50%) patients were being treated in the Orexin-INC group. Postoperatively, there was a reduction in those being treated, which was comparable between the two groups. However, there were both acute (one and five days) and long-term (six and 12 months) changes in lipid profiles, with overall greater changes in the Orexin-INC group relative to the Orexin-DEC group.

Over the long-term (at six months and 12 months), there was a significant continued reduction of fasting cholesterol, triglyceride and LDL-cholesterol, again with greater changes in the Orexin-INC group, while HDL-C increased (Figure 2).

Figure 2. Rapid and long-term improvement in lipid profile after BPD-DS bariatric surgery.

The researchers write that the major findings from the study include; early acute changes in orexin levels prior to weight loss, changes are present in some but not all patients, and early orexin changes were maintained consistently within subjects throughout the observation period (one year).

In addition, they note that comparable long-term weight decreases, the early changes in orexin are associated with differential improvements in lipid and glucose profiles throughout the one-year postoperative period.

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