Ghrelin and Weight Loss in Obesity

Obesity is a chronic disease that is causally related to serious medical illnesses such as type 2 diabetes mellitus, hypertension, hyperlipidaemia, sleep apnoea and orthopaedic complications.

Based on evidence of the potent orexigenic action of ghrelin, its levels were at first expected to be increased in obesity. On the contrary, ghrelin levels turned out to be inversely related to body mass index.

At present, the exact peripheral signals leading to a reduced ghrelin secretion in obesity have not yet been identified. The most likely hypothesis is that low ghrelin levels in obesity might represent a signal to the hypothalamic centres regulating food intake that energy stores are filled [34].

Ghrelin gene polymorphisms have been described by several groups; linkage analysis studies, however, failed to prove a solid association between ghrelin and obesity [76,93,94].

While diet-induced human obesity, as well as polygenic (e.g. Pima Indians) or monogenic (e.g. MC4-R defect) causes of human obesity all present with low plasma ghrelin levels [34,77], severely obese patients with PWS show markedly increased plasma ghrelin levels [32,33,95]. PWS is the most frequent known cause of genetically induced obesity and is associated with a defect on the short arm of chromosome 15, while the exact pathophysiological mechanisms leading to the obesity syndrome in PWS remain unclear [96]. Apart from their adiposity, patients with PWS suffer from a severe hunger syndrome, decreased locomotory activity, impaired GH secretion, increased sleepiness and relative hypoinsuli-naemia [97, 98]. Although it appears intriguing that hyperghrelinaemia in PWS might be responsible, at least in part, for the majority of symptoms characterising this disease, the biological significance of the link between ghrelin and PWS remains at present unexplained [32,33,95].

However, independently from whatever the pathophysiological mechanisms underlying ghre-lin hypersecretion in PWS may be [99], several data indicate that ghrelin hyposecretion in essential obesity is only a functional impairment.

In fact, a significant increase of ghrelin levels has been reported after weight loss induced by either diet or lifestyle modifications [77].

Given the potent orexigenic effect of ghrelin, the implication of these findings is that an increase in ghrelin levels caused by weight loss may help to promote regaining weight. In this context, it has been hypothesised that methods of weight loss that fail to trigger a compensatory rise in ghrelin levels might help sustain weight loss on a long-term basis.

Among the different surgical treatments of obesity, Roux-en-Y gastric bypass (RYGB) surgery is the most effective approved treatment for morbid obesity [100,101]. This procedure restricts the gastric volume that is capable of storing food, bypassing most of the stomach and all of the duodenum (i.e. the majority of ghrelin-producing tissue) with a gastrojejunal anastomosis.

Importantly, the ultimate mechanisms by which this technique induces weight loss have not yet been defined but, notably, restrictive vertical-banded gastroplasty, which induces similar reduction of gastric volume, is less effective at maintaining long-term weight loss [100].

Interestingly, patients who undergo RYGB typically experience a generalised loss of appetite, suggesting that different mechanisms influencing appetite beyond simple gastric restriction may occur after this surgical treatment [100]. For these reasons, the existence of peculiar alterations of ghrelin secretion after RYGB has been hypothesised.

In fact, most authors reported that, despite inducing a marked weight loss, RYBG surgery is not followed by normalisation of ghrelin secretion and, according to some authors, even induces a further reduction of its circulating levels [104]. On the other hand, weight loss induced by bil-iopancreatic diversion [102] or adjustable gastric binding [103] is associated with an increase of circulating ghrelin levels, in agreement with the reported inverse relationship between BMI and ghrelin levels [104].

The pathophysiological mechanisms leading to the apparently inappropriate ghrelin hyposecre-tion after RYBG have not been described so far. The most convincing hypothesis is that the majority of ghrelin-producing cells, when chronically isolated from contact with enteral nutrients, undergo overriden inhibition [104]. According to this model, the condition of an empty stomach and duodenum, which acutely stimulates ghrelin production, paradoxically inhibits it when present continuously after RYGB [101].

If this model is valid, the location of the staple line that partitions the stomach into upper and lower compartments in RYGB may be a critical determinant of ghrelin suppression [101]. In fact, the persistence of some ghrelin-producing cells in intermittent contact with food would fail to be silenced through overriden inhibition.

This hypothesis would explain why bariatric surgery that does not exclude major ghrelin-producing tissues, such as the fundus, from contact with food would be ineffective at suppressing ghrelin.

Normal concentrations of ghrelin might also be sustained in RYGB variants with a short biliopan-creatic intestinal limb because intermittent retrograde flow of ingested nutrients from the anastomosis could reach the duodenum and stomach, where ghrelin is mainly produced [102,104].

An alternative hypothesis to reconcile discordant reports regarding the effect of different techniques of bariatric surgery on ghrelin levels pertains to variable surgical treatment of the autonomic nervous input to ghrelin-producing tissue in the foregut, since an important modulatory role of gastric vagal (parasympathetic) innervation on ghrelin secretion has been clearly demonstrated [105].

Diet Tweak System

Diet Tweak System

Trying To Lose Weight Can Be Tough. But... Not Losing Weight and Gaining What You Lost Back, Sucks. If you've ever felt that no matter what you do to lose weight nothing seems to work. If you've ever felt that there has got to be some kind of a system or way to lose weight...but just have not found it yet.

Get My Free Ebook

Post a comment