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Gene, Diet, Disease

ADIPOQ, Obesity and Type 2 Diabetes

Genetic variants of ADIPOQ can render their carriers susceptible to obesity and T2DM. The genetic risks for obesity and T2DM can be reduced with calorie restriction and low-fat diets.

ADIPOQ is the gene that encodes the protein adiponectin, one of the hormones that are secreted exclusively by adipocytes (fat cells). Adiponectin reaches its main targets - muscle and liver cells through blood circulation and binds to specific cell surface receptors to activate fat burning and glucose utilization, leading to overall energy expenditure and ultimately reduced fat mass and improved insulin sensitivity. Blood adiponectin concentration is relatively constant in an individual and varies between people as the result of long-term influence by many factors such as genetic makeup, body weight, gender, and health status (Fig. 1).

Figure 1. Factors that regulate the adiponectin levels (Adopted from Trujillo & Scherer, 2005).
In general, a lower serum adiponectin concentration correlates with increased risk for obesity and insulin resistance and consequently increased risk for T2DM (Type 2 diabetes mellitus) while a higher concentration correlates with decreased risk (Fig. 2).

Figure 2. Correlations between serum adiponectin concentration and BMI in healthy human population (left panel, adopted from Poppitt et al, 2008) and insulin resistance in obese and T2DM patients (right panel, adopted from Izadi et al, 2011).

ADIPOQ gene is located on chromosome 3q27, a region identified as susceptibility locus for T2DM by genome wide scans. Several rare mutations in ADIPOQ gene that predispose the risk for obesity and T2DM have been identified.  In addition, many common variants have been associated with obesity and T2DM in specific human populations.  Some associations are strong in overweight or obese populations or certain ethnic groups but are weak or non-exist in other populations.  Among these common variants, two haplotypes stand out.  A haplotype refers to a combination of variants at two or more specific sites in the same DNA molecule. For the convenience of description, these two haplotypes are referred to as the promoter region and the gene region risk haplotype respectively hereafter.

The promoter region haplotypes are determined by genetic variations at two sites located in the promoter region of the ADIPOQ gene.  A promoter is the DNA sequence that controls the turn on or turn off of the gene.  The two sites are the -11391 site and the -11377 site, referring respectively to the two sites 11,391 and 11,377 nucleotides upstream of the ADIPOQ gene coding sequence. The promoter region risk haplotype occurs when the DNA sequence at both sites are nucleotide G.  Homozygous carriers (people who carry two copies) of this risk haplotype have on average about 40% decreased serum adiponectin level than non-carriers.  Heterozygous carriers (people who carry one copy) of this risk haplotype have on average about 20% decreased serum adiponectin level than non-carriers.

The gene region haplotypes are determined by genetic variations at two sites located inside the ADIPOQ gene. When the DNA sequence at the +45 site is T and the +276 site is G, the gene region risk haplotype occurs. Homozygous carriers (people who carry two copies) of this risk haplotype have on average about 20-30% decreased serum adiponectin level than non-carriers.  Heterozygous carriers (people who carry one copy) of this risk haplotype have on average about 10-15% decreased serum adiponectin level than non-carriers.

Up to 59% and 26% of the general population carry the promoter region risk haplotype and the gene region haplotype respectively (Table 1).

Table 1. Distribution frequency of the risk haplotypes in major ethnic groups.

Risk haplotypes Caucasians Africans Asians Hispanics
Promoter region 50-59%   41% 56%
Gene region 25% 15% 23-26%  

Due to associated lower adiponectin levels, thus less fat burning and less glucose clearance activities, the risk haplotypes renders their carriers higher risks to gain weight and to develop insulin resistance and consequently T2DM in response to excess calorie, high glycemic index and high-fat diet.  Therefore, for a normal weight and healthy risk haplotype carriers, avoiding excess calorie intake, taking low-fat and low glycemic index food are good health management strategy.  For the overweight and obese risk haplotype carriers, calorie restriction and active life style are the best choices to weight loss.

Besides the risk haplotypes at the promoter region and gene region, there are also haplotypes that are associated with increased adiponectin level. Gene-dietary interaction studies show that carriers of these haplotypes are better off with high-MUFA diets in order to prevent weight gain. As described in the Omega-3 and Omega-6 Fatty Acids review, olive oil and canola are two of the good sources of MUFAs (monounsaturated fatty acids).

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