Have we got the guts to maintain target weight?

With the obesity epidemic showing no signs of declining, understanding the mechanistic secrets behind losing body fat is highly relevant. In this issue of Acta Physiologica, Gerstenberg, and co-workers¹ examine an increasingly important paradigm relating to lifestyle modifications that can induce and maintain body weight loss. Their studies cenetred on the secretion of appetite-regulating hormones from the gut of caloric-restricted rats fed a high-fat diet (HFD). In this setting, calorie restriction led to a 20% reduction in body weight in HFD rats at the time of experimentation. We are already aware that the secretion of appetite-inhibiting hormones is reduced in human obesity.² However, uncovering whether this effect is reversible following weight loss was the primary objective of Gerstenberg and colleagues.¹

The chief experimental model employed by the investigators is the perfused rat small intestine.³ The gut is the largest endocrine organ of the body and fundamental for the secretion of numerous appetite-regulating hormones. Earlier approaches to investigate gut hormone secretion predominantly involved primary or clonal cell lines as well as assessing hormone concentrations in plasma. The isolated intestinal perfusion model bridges the gap between these somewhat imperfect approaches, allowing for immediate assessment of dynamic hormone secretion under various stimuli in the absence of confounding factors.³ Secretory concentrations of cholecystokinin (CCK), gastrin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), neurotensin (NT), and somatostatin (SST), all gut-derived hormones known to suppress appetite, were measured using validated in-house radioimmunoassay's (RIAs).¹ To this end, the experimental tools employed here are the envy of physiology and biochemistry laboratories worldwide. That said, there were notable variations in baseline and stimulatory secretion profiles of some of the hormones studied, which may somewhat distort data interpretation. Whether this reflects model-specific issues, intra-assay variations of RIAs used, or simply the inherent unpredictability of gut hormone secretion remains to be elucidated. Indeed, gut hormone-secreting cells have a relatively rapid turnover rate and shown to possess the ability to switch hormone expression along the crypt-to-villus length.⁴ In addition, the authors also examined gene expression of gut hormone nutrient transporters and markers of gut barrier integrity along the full length of the intestine.

The main finding from the study was that a 20% reduction of body weight in HFD rats did not affect the secretion of gut-derived CCK, gastrin, GIP, GLP-1, NT, and SST when compared to HFD control rats.¹ In addition, enteric gene expression was also not influenced by this significant weight loss, although expression of the fructose transporter GLUT5 was upregulated in the duodenum alongside a small increase in the villus length, but neither modification was accompanied by obvious physiological effects. One important limitation that should be considered when deciphering the data presented by Gerstenberg et al¹ is the lack of a comparative group of lean control rats. It remains unclear if HFD-induced obesity caused impairments in the secretion of the hormones investigated in this setting. Although, there is good evidence to suggest impaired activity of rodent gut hormone secretory cells under prolonged HFD stimulation.⁵ Moreover, in the human setting, weight loss is often linked to consuming smaller portions of the same foodstuffs rather than extreme changes in dietary habits, very much akin to the calorie restriction protocol employed.¹ However, a complete investigation of all gut-derived appetite-inhibiting hormones was not undertaken, with the obvious omission of oxyntomodulin and PYY. In addition, changes in levels of “hunger hormones” such as ghrelin were not considered, albeit this is a gastric hormone. Finally, many gut-derived derived hormones, and especially GIP,⁶ are released in response to lipid uptake. The procedure employed by Gerstenberg et al¹ lacked analysis of responses following fat stimulation. The reason for this is that the main route for drainage of dietary lipids and lipid-soluble nutrients form each villus in the small intestine, the lacteals, does not function effectively in the chosen system. Ultimately, adaptations of the experimental setup are still required to permit analysis of natural lipid handling and subsequent effects on hormone secretion. Despite these restrictions, the authors present convincing evidence of a lack of effect of body weight loss on appetite hormone secretory profiles.

Regrettably, weight loss interventions employed in the human setting, although initially can be effective, often result in relapse.⁷ The current work¹ suggests that alterations in the secretion of appetite-inhibiting hormones from the gut are unlikely to contribute to this initial weight loss in obesity, and may even be a factor in weight regain. The search for endogenous gut-derived mediators of weight loss in obesity continues. Losing weight can be challenging, but it appears guts are not required to maintain target body weight—well, at least in rats.

The author declares no potential conflicts of interest relevant to this article.