Long-term effects of Garcinia cambogia/Glucomannan on weight loss in people with obesity, PLIN4, FTO and Trp64Arg polymorphisms

Obesity may be defined as abnormal or excessive fat accumulation that impairs health [1]. This illness is a global pandemic with a high prevalence in western societies that is also fast spreading across developed countries [1]. In 2008 was estimated that about 1.46 billion people suffer from overweight in the world and of them 504 million were people with obesity [2]. Obesity and its comorbidities represent a social-economic burden that reduce life expectancy and it has been associated with suffering from osteoarthritis, fatty liver, cardiovascular disease, digestive problems, diabetes mellitus type 2 (DM2) and even different kinds of cancer [2‐4]. In childhood, in which overweight and obesity numbers are dramatically increasing, other pathologies such us orthopedic complications, breathing problems and psychological disorders have also been reported [5]. For practical reasons, overweight is defined as body mass index (BMI, weight in kg divided by height squared m², also kwon as Quetelet’s index) between 25 and 30 and obesity when BMI > 30 [6].

The causes of obesity are several, although and increase in calories ingest together with sedentary way of life are intrinsically associated to its development being both of them preventable [7]. Other causes also linked to obesity are socioeconomic factors, birth weight, pollution, stress and microbial infections [8, 9]. Genetic background also plays a key role in obesity development [10]. Studies carried out in twins reported that obesity might be heritable component between 40 and 75% [11] and multiple genetics syndromes has been related to obesity [12]. Thus, some polymorphism present in genes such as Fat mass and obesity-associated (FTO), Perilipin (PLIN) and β-adrenergic receptor 3 (ADRB3) have been studied associated with obesity development. FTO is located in humans in chromosome 16 and codifies the enzyme 2-oxoglutarate nucleic acid dependent demethylase that is expressed in the hypothalamus and regulates food intake [13]. Variations of FTO gene has been associated to an increase in food intake [14]. In particular, polymorphism rs9939609 A/T has been association to regulation of satiety feeling [15]. On the other hand, it has been reported that PLIN gene (located in chromosome 15) and with several described polymorphism such as PLIN1 6209 T → C, PLIN4 11482G → A and PLIN6 14995A → T have been associated with obesity development or protection [16, 17]. Perilipin 1, is a protein present in adipocytes that play an important role in fat accumulation and mobilization, covering the lipids droplets protecting them from lipase enzymatic action [18]. In addition, ADRB3 polymorphism Trp64Arg has been strongly associated to obesity and DM2 [19]. Activation of this receptor plays a role in lipolysis and thermogenesis regulation [15].

Different strategies have been proposed to deal with obesity epidemic. Caloric restriction combined with exercise are the most used one against this disease and in cases of extreme obesity, surgical intervention is recommended [20]. Other strategies include the use of herbal medicinal products from Garcinia camboia (GC) and Glucomannan that have reported to be positive in relation to control and loss weight [21‐25]. GC is a fruit that naturally grows in South Asia and Indian forest with a high content of hidroxicitric acid (AHC). AHC inhibits lipogenesis impairing hydrocarbon conversion in lipids. AHC produces the inhibition of ATP-citrate liase, an enzyme that is required for the first step in lipogenesis process. AHC action also increments glycogen hepatic deposit, decrease appetite and reduces weight gain [26]. On the other hand, GNN is a fiber composed of β 1,4-linked D mannose and D-glucose monomers extracted from a tuber called Amorphophallus konjac [27]. In spite of GNN mechanism of action has not yet been fully understood, some authors have suggested, that given that GNN is able to absorb 50 times its weight in water volume, this fiber would fill up the stomach resulting in a delayed gastric emptying causing a satiety feeling and reducing the appetite [28].

In this work, we aimed to assess whether a controlled diet supplemented with GC and GNN was able to reduce weight after 3 and 6 moths in people with overweight or obesity. We also wanted to evaluate if this reduction was modified by the presence in the patients of different genetic polymorphism related to FTO (rs9939609 A/T), PLIN4 (11482G > A) and ADRB3 Trp64Arg.

Here, we wanted to expand previous studies in which treatment with GC and GNN were combined to reduce obesity [31]. In this previous study, that was a double blinded randomized study with a placebo and treated group, it was reported that GC and GNN administration reduced cholesterol levels but without affecting anthropometric or calorimetric values. Now, we show that administration of a combined therapy of GC and GNN to 214 people with overweight or obesity and some associated comorbidities such us dyslipidemias, hypertension and DM2, reduce at 3 and 6 months the weight (14 and 16%), fat mass (7 and 12%), visceral fat (9 and 15%), glucose (3 and 6%), cholesterol (8 and 13%), triglycerides (10 and 15.3%) and increase BMR measured by indirect calorimetry (2 and 4%). Several reports support that GC administration reduces weight [34, 35] although other has not found enough evidence [36] or doubt about its long term effects because there are not reported on more than 12 months of administration [26]. These differences, even some reported minor side effects, might be related to the different compositions of available GC extracts and administered doses [37]. On the other hand, GNN has also proved to reduce weight [38] although other studies did no find such association [39]. These differences might be related to variability of patient inclusion criteria in each study, and as in the case of GC to the different composition of Glucomannan extracts used. Of note, it is important to underline that here, the combined treatment, is able to reduce weight, fat mass and visceral fat independently of sex, age and previous diseases without having aby adverse effects in the patients which makes this treatment suitable for a broad population segment.

On the other hand, it has been reported that success of obesity therapies has been influenced by individual variability mainly based on differences on life style and genetic background [20, 40]. For these reason, we also aim to study the influence of different polymorphism associated to obesity risk with a treatment with GC and GNN to reduce weight. Thus, the second objective or our work was to determine whether presence of different polymorphism might affect the result of GC and GNN combined treatment. When we analyzed the results by polymorphism effect, we found that there were an attenuated weight reduction, visceral fat and fat mass in carriers of FTO (rs9939609 A/T), PLIN4 (11482G > A) and ADRB3 (Trp64Arg) polymorphism at the two different times. Polymorphisms in PLIN and ADRB3 use to produce alteration in lipolysis mechanism (i.e. decreasing it) [41] whereas treatment with GC and GNN have demonstrated to produce loss weight particularly increasing lipolysis [42]. Thus, it would be reasonable to hypothesize that a reduction in lipolysis rate in patients with these polymorphisms might have hampered the lipolysis effect trigger by GC and GNN influencing the outcome of the treatment.

PLIN gene codified perilipin 1 protein that is phosphorylated by protein kinasa A. Perilipin 1 phosphorylation facilitates the action of hormone sensitive lipase, an enzyme that play a key role in lipolysis. Several polymorphisms in this gene has been associated to obesity [41, 43]. Thus, patients carriers of PLIN1 (6209 T > C; rs2289487) and PLIN6 (14995A > T; rs1052700) polymorphism have shown to response better to anti-obesity treatment [16]. On the contrary, and in agreement with our results, those patients carriers of PLIN4 (11482G > A) response worse to weight loss treatments [44].

Regarding ADRB3, this receptor plays an important role in the lipolysis activated by catecholamine signaling. The change Trp64Arg produces that ADRB3 does not reach the maximal generation of cyclic AMP upon activation and thus reduce lipolysis [45]. Accordingly, in our study, carriers of this polymorphism did not reduce weight, fat mas and visceral fat at the same rate that non-carriers subjects. However, although levels of triglycerides and cholesterol were increase compared with non-carrier patients, these levels did not reach a statistical significance.

On the other hand, FTO polymorphism rs9939609 is associated to a low satiety feeling after meals rather than a regulation of basal metabolic rate [45]. Here, we found that patients with this polymorphism does not reduce weight, visceral fat and fat mass as normal patients. These results might be explained because these patients has a tendency to increase calorie intake, hindering treatments effects. Considering that presence of the different polymorphism studied in this work influence the grade of losing weight, fat mass and visceral mass, it would be of the utmost importance to previously known the genetic background of each subject to adjust the treatment (perhaps increasing dose of GC or GNN) to obtain a better outcome.

Taken together these data, we conclude that treatment with GC and GNN of people with overweight or obesity with different sex, age and affected by difference metabolic diseases decrease weight, fat mass, visceral fat, glucose, triglycerides and cholesterol levels together with an increasing basal metabolic rate without having any adverse effect. Given that presence of different polymorphism such as PLIN4 (11482G > A), FTO (rs9939609 A/T) and ADRB3 Trp64Arg might hamper this beneficial effects, a patient genetic study focus on the presence of these polymorphisms might be advisable previously to establish a treatment and thus get a better prediction of response treatment.