**12. Receptors and signaling**

Two receptors have been identified that bind adiponectin: Adipo R1 and Adipo R2. AdipoR1 was first identified when encoding cDNA was isolated from human skeletal cDNA library by screening for adiponectin binding [36]. The AdipoR2 was identified later due to its striking homology to AdipoR1. Both are surface membrane proteins [36] and have homology to G protein-coupled receptors.. These receptors contain seven transmembrane domains, but are structurally and functionally distinct from other known GPCRs (G-protein-coupled recep‐ tors[37]. The receptors have different affinities to the various molecular forms of adiponectin. AdipoR1 and AdipoR2 are found in liver, muscle and adipose tissue in humans; however AdipoR1 is predominantly expressed in skeletal muscle whereas AdipoR2 is more predomi‐

nant in the liver [36]. AdipoR1 is a high-affinity receptor for globular adiponectin as well as having a lower affinity for full length adiponectin. In contrast the AdipoR2 receptor has an equal intermediate affinity for globular and full length HMW adiponectin [36]. The receptors affect a very important cellular metabolic rate control point, by targeting AMP-activated protein Kinase (AMPK), downstream. AMPK is a stress induced kinase that is activated in response to depleting Adenosine triphosphate (ATP) or increasing Adenosine monophosphate (AMP) levels. AMPK activates ATP and generates catabolic processes such as fatty acid breakdown and glycolysis and shuts down ATP-consuming processes such as lipogenesis [37]. Expression of these receptors is correlated with insulin levels [24]. A review of studies involving the adiponectin receptors suggests that they may have an important role in adipo‐ nectin physiology. Key findings suggest that changes in expression of AdipoR isoforms in skeletal muscle (rather than total circulating adiponectin concentrations) may be of physio‐ logical importance [38]. More recently, by means of expression cloning, T-cadherin has been recognized as an adiponectin receptor on vascular endothelial cells and smooth muscle [36]. The expression of this cadherin molecule is known to be correlated with atherosclerosis [33].By genomic sequence analysis, Saito et al. determined that the ADIPOQ gene spans 16 kb,contains 3 exons and 2 introns and the promoter lacks a TATA box(a sequence involved in the process of transcription). The exon-intron organization of this gene was very similar to that of obese gene,encoding leptin. Saito et al. reported that the ADIPOQ gene was located on human chromosome band 3q27using chromosome mapping of this gene by fluorescence in situ hybridization (FISH) taking genomic DNA fragment as a probe [39]. It is reported that a mutation in this gene is associated with low serum adiponectin levels and T2DM[41].

and high-molecular weight forms of adiponectin are the predominant forms in serum whilst

There are four distinct regions of adiponectin. The protein starts with a short signal sequence which acts to target the hormone for secretion outside the cell, then it leads into a short region that is variable between species, followed by an amino-acid region that shows similarity with collagenous protein, and finally ending with a globular domain. The three dimensional structure of its C-terminal globular domain is similar to that of tumor necrosis factor–alpha (TNF-α), even though there is no sequence homology at the primary structure level. [32].

Initially, three adiponectin molecules associate through disulphide bonds within the collage‐ nous domains of each monomer to form bouquet-like higher order structure, a homotrimer.

The levels of the higher order structures are sexually dimorphic [34], where females have increased proportions of the high-molecular weight forms. The varying forms have altered biological activity and therefore may also have separate functions. The gC1q domain and the trimeric forms of adiponectin activate AMP Kinase in skeletal muscle and lead to increased fatty acid oxidation and reduction in glucose concentrations, whereas the hexameric and full length HMW forms are thought to activate nuclear factor kappa B (NF-κB) pathways [35]. The proportion of HMW adiponectin within adipose tissue is higher than in blood plasma, suggesting regulation at the level of secretion and is a mechanism of adiponectin complex distribution. All isoforms of the molecule are stable in circulation having a relatively longer

Two receptors have been identified that bind adiponectin: Adipo R1 and Adipo R2. AdipoR1 was first identified when encoding cDNA was isolated from human skeletal cDNA library by screening for adiponectin binding [36]. The AdipoR2 was identified later due to its striking homology to AdipoR1. Both are surface membrane proteins [36] and have homology to G protein-coupled receptors.. These receptors contain seven transmembrane domains, but are structurally and functionally distinct from other known GPCRs (G-protein-coupled recep‐ tors[37]. The receptors have different affinities to the various molecular forms of adiponectin. AdipoR1 and AdipoR2 are found in liver, muscle and adipose tissue in humans; however AdipoR1 is predominantly expressed in skeletal muscle whereas AdipoR2 is more predomi‐

smaller complexes such as the trimer are virtually undetectable. [31].

The trimers continue to self-associate and form hexamers [33].

**10. Monomeric structure**

112 Treatment of Type 2 Diabetes

**11. Higher order structures**

half life (half-life of ~15hrs) [24].

**12. Receptors and signaling**

It has been reported that blood concentrations of adiponectin fall from 20-50% in humans and mice respectively with the administration of insulin, thus implying that the effect of insulin to lower adiponectin levels may involve inhibition of adipocyte secretion. Plasma adiponectin levels have also been shown to be decreased in an obese rhesus monkey model that frequently develops Type 2 Diabetes [42] Many prospective studies [43-45] have shown that lower adiponectin levels are associated with a higher incidence of diabetes in humans and more importantly the decrease in plasma adiponectin levels was in parallel with the decrease in insulin sensitivity [25]. This finding is further supported by a recent analysis of 13 prospective studies, which found that higher adiponectin levels were associated with a lower risk of Type 2 Diabetes across diverse populations [45-46].

The levels of serum total cholesterol and triglycerides are comparatively lower for local Libyan subjects when compared to South Asians and Non South Asians.[47] The serum level of total HDL cholesterol is also low in Libyan subjects probably due to the lowered levels of total cholesterol and triglycerides.[47].

A marked increase was observed in non-HDL cholesterol in obese individuals compared to the control group.[48] and there was a marked fall in HDL cholesterol indicating that dyslipi‐ demia is prevalent in local Libyan subjects

This preliminary study indicates that the distribution of fat in Libyan population varies from other populations. There is a marked increase in total as well as abdominal adiposity indicated by anthropometric measurements. The serum level of adiponectin is low in this population along with comparatively HDL cholesterol with a marked increase in non-HDL cholesterol. Therefore further studies are being carried out to bring out the nature unique ethnic diversity in the population as well as to recommend that an overall reduction of body weight in the population need to be considered to lower risk of metabolic disorders.

Apart from these observations the serum levels of adiponectin were found to be lower for the Libyan subjects and its level was increased in T2DM subjects.

This observation seems to suggest whether serum adiponectin level in Libyan subjects can be taken as a biomarker of ethinic heterogeneity.
