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Adiponectin secretion in HIV-infected subjects with or without antiretroviral treatment and illicit substance use: clinical review and update.

List of Abbreviations:

Acrp30: Adiponectin; HAART: Highly Active Antiretroviral Therapy; HIV: Human Immunodeficiency Virus; NRTI: Nucleoside Reverse Transcriptase Inhibitor; NNRTI: Non-Nucleoside Reverse Transcriptase Inhibitor; InSTI: Integrase Strand Transfer Inhibitor; PI's: Protease Inhibitors; d4T: Stavudine; EVG: Elvitegravir; RPV: Rilpivirine; NVP: Nevirapine; EFV: Efavirenz; LPV/r: Lopinavir/ ritonavir; PPAR-[gamma]: Peroxisome-Proliferator Activated Receptor gamma; SREBP-1: Sterol Regulatory Element Binding Protein-1; C/ EBP-[alpha]: CCAAT Enhancer Binding Protein alpha; FABP-4: Fatty Acid Binding Protein 4; TNF-[alpha]: Tumor Necrosis Factor alpha.


The white adipose tissue constitutes a major endocrine organ that functions to produce biologically active substances termed adipokines, which exert either local and/or systemic effects [1-3]. Among these many adipokines includes; adiponectin, leptin, resistin, visfatin, adipsin, apelin, cheperin and retinol binding protein-4 (RBP-4) [2,4]. The adipocytokine, also known as adipocyte complement related protein (Acrp30) or gelatin-binding protein 28 (GBP-28); is a 30 kDa protein secreted exclusively from the adipose although some other tissues including the placenta are involved in its secretion [5,6]. Discovery of Acrp30 was through cDNA cloning techniques, with the adipocytokine being a protein product of apM1 gene that represents the most abundant adipocyte gene transcript [7].

Adiponectin modulates a number of endocrine-like and metabolic functions [8,9]. As such, reduction in circulating levels of Acrp30 is associated with obesity and cardiovascular disease [10], whereas higher levels are exhibited in obese individuals losing weight [11]. Hence, decreased production of adipokines by adipose tissue has been reported to predispose artherosclerosis and obesity-related pathological conditions including diabetes mellitus, endothelial dysfunction, cardiovascular disease and chronic kidney disease [12-14]. Contrastingly though, HIV-infected subjects with or without antiretroviral use display distinct profiles of Acrp30 expression relative to uninfected individuals. For instance, reduced Acrp30 levels have been documented in HIV-positive patients despite low fat mass [15]. Additionally, certain ART regimens are revealed to cause a decline in circulating Acrp30 levels [16].

The illicit substance using population accounts for a small group of individuals, yet responsible for high HIV burden globally [17-19]. The practice of illicit drug and substance use has been revealed to heighten systemic inflammation and immune activation especially during HIV infection [20-22]. However, complex interaction of illicit drugs and inflammatory profiles of metabolic derangement including Acrp30 has not been critically evaluated among HIV-infected illicit substance users. Although, a limited number of studies have shown illicit drugs such as heroin to cause a dysregulated production of host circulating adiponectin levels [23,24].

Hence, all aspects put to consideration; there is accumulating evidence that Acrp30 serves multiple roles in striking the balance between glucose homeostasis/regulation and metabolic abnormalities both in normal and diseased states. This review compiles data from various research articles on Acrp30 expression and action particularly with emphasis on the adipocytokine kinetics including inflammatory responses during instances of HIV-infection, antiretroviral treatment and illicit substance consumption, which will be critical in understanding contribution of each agent towards systemic metabolic dysfunction, with a common aim of improving treatment outcomes for HIV-positive illicit substance consuming patients.

Regulation of adiponectin expression

Adiponectin an adipose tissue-specific protein is normally under transcriptional control of adipogenesis regulators comprising; PPAR-[gamma] (peroxisome-proliferator activated receptor gamma), SREBP-lc (sterol regulatory element binding protein-lc), C/EBP-[alpha], (CCAAT enhancer binding protein alpha) and ID-3 protein [25-28]. Receptors that serve to mediate effects of Acrp30 comprise AdipoRl and R2 [29,30]. It is noteworthy that various anti-diabetes drugs more specifically thiazolidinedione (TZD) class to which pioglitazone and rosiglitazone (PPAR-[gamma] agonists) belong, are characterized with Acrp30 high inducing capacity [31-33]. Therefore, increased Acrp30 expression modulates beneficial effects of this class of therapeutic agents.

More importantly, wide ranging post-translational modification which entails hydroxylation and glycolysation is critical for Acrp30 assembly and subsequent formation of functional oligomeric complexes [34-37]. Hence, following Acrp30 secretion that is regulated particularly by endoplasmic reticulum (ER) proteins ERp44 and oxidoreductase Erol-La [38,39], the adipocytokine is found circulating freely within plasma in three oligomeric forms namely, high molecular weight (HMW; oligomer), medium molecular weight (MMW; hexamer) and low molecular weight (LMW; trimer) [40] (Figure 1). However, host circulating levels of this adipocytokine are dependent on various factors including sex, metabolic status and body fat distribution [41-43]. Additionally, the state of oligomerisation is vital as it regulates both signal transduction pathway and overall biological functioning of Acrp30 [34,36,44,45]).The three oligomeric complexes together are collectively termed as full-length adiponectin (fAd) [46].

Several transcription factors (top left) which mediate adiponectin gene transcription are regulated to increase (thiazolidinedione, TZD) or decrease (tumor necrosis factor-alpha, TNF-[alpha]) adiponectin expression. Monomeric adiponectin (mAd) is post-translationally modified and further oligomerized to form trimers (low molecular weight, LMW), hexamers (medium, MMW) and oligomeric (high, HMW) forms. Various mechanisms (bottom right) mediate this oligomerization and secretion resulting in secretion of HMW, MMW, and LMW forms [47].

Adiponectin expression and action in non-obese/lean subjects

Normally, the circulating levels of Acrp30 show reciprocal relationship with the proportion of body fat composition [48]. Thus, low systemic concentrations of this adipocytokine have been described among obese subjects relative to their lean counterparts [49]. The subcutaneous adipose tissue (SAT) has been found to be associated with higher Acrp30 production compared to the visceral fat component of adipocytes [50]. Additionally, SAT accounts for roughly 85-90% of adipose tissue amongst lean persons. Therefore, these revelations may essentially justify the paradoxically higher levels of circulating Acrp30 reported amongst lean against obese subjects. Production of Acrp30 in lean individuals exerts effect on glucose metabolism through prevention of fatty acid mediated inhibition of glucose utilization by muscle cells [51], therefore minimizing the likelihood of obesity.

Adiponectin and obesity

Adiponectin has been shown to regulate multiple metabolic processes including glucose and lipid metabolism [52], hence fluctuations in circulating levels of this adipocytokine is implicated in various clinical challenges. For instance, decreased systemic Acrp30 levels that is experienced among obese subjects despite a high mass of adipose tissue is a driver for metabolic syndrome that is often characterized by dyslipidaemia, atherosclerosis, cardiovascular disease, endothelial dysfunction, insulin resistance (Type 2 diabetes) among others [10,53]. Hence, Acrp30 expression is observed to be under feedback inhibition during instances of obesity.

Immunologically, the inflammatory responses, more specifically a T helper-1 (Th-1) mediated pro-inflammatory milieu by tumor necrosis factor-alpha (TNF-[alpha]), is identified as a primary cause of suppressed Acrp30 expression in obese/diabetic subjects [54-56]. However, a rise in Acrp30 levels following weight reduction is demonstrated to lower TNF-[alpha] mediated inflammatory responses through activation of cAMP protein kinase A signaling pathways [57]. Likewise, over-expression of myelomonocytic cells has been shown to impair metabolic function in adipose tissue, although Acrp30 regulates this activity by inhibiting proliferation of these cells through apoptosis induction [58]. Overally, activity of these inflammatory mediators defines their role in promoting pathophysiology of obesity [59].

On the other hand, the precise mechanisms mediating development of atherosclerotic vascular disease among obese subjects remains largely undefined. However, Acrp30 levels become increased and localize within injured vascular walls as opposed to intact vessels which functions to suppress macrophage-to-foam cell transformation thereby regulating/inhibiting plaque build-up and resultant atherosclerosis [60,61]. These activities portray Acrp30 as a crucial adipocytokine modulating anti-atherogenic effects besides counteracting the aforementioned adipose tissue inflammation.

Decreased Acrp30 secretion (hypo-adiponectinaemia) in obesity has been implicated with promotion of insulin resistance [62]; however, the underlying mechanisms modulating Acrp30 activity on insulin metabolism have not been well elucidated. Nonetheless, it has only been speculated that Acrp30 intensifies the expression of molecules that control fatty acid oxidation and energy dissipation within skeletal muscle thereby lowering triglyceride concentrations in this muscle [63]. Additionally, reduced fatty acid influx into the liver as well as gluconeogenesis is also shown to under control of Acrp30 [64] (Figure 2). To add further, more sub-physiological levels of insulin are produced within isolated hepatocytes to suppress endogenous glucose production [64,65]. Cooperatively, this accumulating evidence depicts circulating Acrp30 as an essential regulator of insulin sensitivity.

Adiponectin in HIV-infected ART-naive subjects

Abnormalities in cytokine and hormone circulating levels, along with their altered metabolism have been observed in HIV infection [66,67]. As such, Acrp30 fails to maintain its inverse relationship with body fat mass during incidences of HIV infection [68], possibly due to adipocyte dysfunction resulting from the effects of HIV virus [69,70]. For instance, HIV-infected ART-naive subjects show considerable depletion of subcutaneous fat tissue which accounts for higher Acrp30 supply relative to visceral fat in humans [50,71]. However, the precise molecular mechanisms through which HIV inhibits Acrp30 production remain elusive, although studies suggest that HIV proteins, particularly protein R suppresses transcriptional activity of PPAR-[gamma], which is associated with regulation of Acrp30 gene expression in human adipocytes [72]. Altogether, these observations suggest that low fat store and underlying inflammation may regulate metabolic markers such as Acrp30 in HIV-infection.

Adiponectin in ART-experienced including, lypodystrophic patients

Human immunodeficiency virus infected individuals on HAART are reported to exhibit markedly reduced Acrp30 levels compared to uninfected persons [73,74]. This has been attributed to changes in adipocyte function with associated lypodystrophy and impaired fat redistribution effects [75,76], possibly resulting from the negative adverse drug reactions of various antiretroviral agents [77]. Therefore, specific antiretroviral medications do exert influence on host plasma circulating Acrp30 levels. In particular, exposure to stavudine (d4T) treatment has been associated with lower plasma Acrp30 levels [16].

Likewise, Efavirenz (EFV), Elvitegravir (EVG) as well as rilpivirine (RPV) repress [78-80], whereas nevirapine (NVP) heightens Acrp30 release from adipocytes [79,81,82]. Interestingly though, some antiretroviral agents such as Maraviroc (MVC) an entry/fusion inhibitor, demonstrates no effect on expression and release of Acrp30 from human adipocytes [83], which may minimize adverse ART effect towards adipose tissue. Therefore, this has been suggested as a potentially beneficial outcome among emerging antiretroviral medication although studies are still ongoing to authenticate this. On the whole, peripheral fat loss and general lipodystrophic syndrome contribute immensely towards circulating Acrp30 dysregulation in HIV-1 infected antiretroviral treatment experienced patients (Table 1).

Illicit substance use and adiponectin production

Multiple clinical studies involving both human and animal experimental models have previously established significant correlations between circulating Acrp30 levels and various-disease related outcomes including insulin resistance, cardiovascular and renal diseases [84,85]. However, Acrp30 expression in HIV-positive illicit substance consumers remains less well defined, although opium addiction has been demonstrated to have a positive association with endocrine system disorders [23]. Nonetheless, substance abuse is an important co-morbidity factor that affects the outcomes of HIV clinical management [86].

Illicit drug and substance use has initially been shown to accelerate HIV/AIDS disease progression [22]. Equally, the practice is also reported to cause a dysregulation in cytokine production [87,88]. For instance, levels of circulating Acrp30 are revealed to be markedly reduced in frequently injecting heroin addicts [23,24]. Hence, drug and substance use suppresses systemic Acrp30 production perhaps through interference with kinetics and signaling pathways of the adipocytokine expression within adipocytes. Additionally, it's also possible that chronic inflammation associated with HIV-infection and illicit substance use promotes increased alterations in adipokine profiles of HIV-infected substance users.

Therapeutic role of adiponectin

A range of studies have demonstrated reduced Acrp30 expression to be linked to diabetes mellitus [89,90], while recovery of this adipocytokine controls insulin resistance by enhancing free fatty acid oxidation, glucose uptake and subsequent utilization [91]. Hence, diabetes medicaments including pioglitazone and rosiglitazone belonging to the TZD class of PPAR-[gamma] agonists are observed to be potent inducers of Acrp30 expression [92-95]. This induction of Acrp30 has both metabolic and cardio-protective effects against diabetes mellitus and cardiovascular disease respectively. The proposed mechanisms that regulate Acrp30 expression by PPAR-[gamma] agonists involves a reduction in triglyceride amounts within the muscle and liver cells as well as preventing adipocyte hypertrophy [63]. Additionally, it's also possible that TZD's heighten Acrp30 mRNA expression through the CCAAT/enhancer-binding protein sites [96]. Essentially, the high expression of Acrp30 is a fundamental mechanism of action that mediates beneficial effects of this diabetes controlling drug class.

Clinical trials involving administration of Acrp30 therapy on animal models controlled for obesity reveals hyperglycaemia and hyper-insulinaemia regulation without even inducing weight loss or gain in a number of this studies [48]. To add further, Acrp30 therapy has been demonstrated to reverse insulin resistance in mice manifesting obesity and lipoatrophy [63], which further potentiates the adipocytokine adoption among therapeutic interventions (Acrp30 replacement therapy) to be considered in HIV-infected lypodystrophic patients as well as obesity subjects during instances of metabolic abnormalities.

Conclusion and Future Directives

Summatively, findings from various studies portray Acrp30 as a critical surrogate marker indicative of numerous metabolic derangements including glucose regulation and fatty acid metabolism. However, future studies should identify and characterize the precise molecular mechanisms leading to altered glucose homeostasis during episodes of HIV infection, antiretroviral treatment and substance use. Additionally, more investigations are warranted in order to potentiate use of circulating Acrp30 levels in assessment of nutritional/metabolic profiles of both HIV-infected, treatment-naive and -experienced patients. More importantly, the role of illicit drug and substance use towards dysregulated production of circulating Acrp30, informs the need to assess drug use history among HIV infected patients with the overall goal of improving antiretroviral treatment outcomes in this population. On the whole, the interplay of signals regulated by Acrp30 defines its net effect as a modulator of metabolic inflammatory responses.

DOI: 10.4172/0974-8369.1000318

Conflict of Interest

The authors have no conflicts of interest to declare.

Authors' Contributions

All authors contributed in drafting, review of article and revising the manuscript. Final version of the manuscript was approved by all authors.


The authors thank Kenyatta University Post Modern library for availing space and permitting accessibility to online databases used to gather relevant information for this review. This work received no specific grant from any funding agency whatsoever.


[1.] Conde J, Scotece M, Gomez R, Lopez V, Gomez-Reino JJ, et al. (2011) Adipokines: biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immunity. Biofactors 37: 413-20.

[2.] Trayhurn P, Wood IS (2004) Adipokines: inflammation and the pleiotropic role of white adipose tissue. British Journal of Nutrition 92: 347-55.

[3.] Galic S, Oakhill JS, Steinberg GR (2010) Adipose tissue as an endocrine organ. Molecular and cellular endocrinology 316: 129-39.

[4.] Maury E, Brichard SM (2010) Adipokine dysregulation, adipose tissue inflammation and metabolic syndrome. Molecular and cellular endocrinology 314: 1-6.

[5.] Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M (1996) Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. Journal of biochemistry 120: 803-12.

[6.] Chen J, Tan B, Karteris E, Zervou S, Digby J, et al. (2006) Secretion of adiponectin by human placenta: differential modulation of adiponectin and its receptors by cytokines. Diabetologia 49: 1292-302.

[7.] Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, et al. (1996) cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPoseMost abundant Gene transcript 1). Biochemical and biophysical research communications 221: 286-9.

[8.] Ouchi N, Parker JL, Lugus JJ, Walsh K (2011) Adipokines in inflammation and metabolic disease. Nature Reviews Immunology 11: 85-97.

[9.] Mattu HS, Randeva HS (2013) Role of adipokines in cardiovascular disease. Journal of endocrinology 216: T17-36.

[10.] Robinson K, Prins J, Venkatesh B (2011) Clinical review: adiponectin biology and its role in inflammation and critical illness. Critical Care 15: 1.

[11.] Madsen EL, Rissanen A, Bruun JM, Skogstrand K, Tonstad S, et al. (2008) Weight loss larger than 10% is needed for general improvement of levels of circulating adiponectin and markers of inflammation in obese subjects: a 3-year weight loss study. European Journal of Endocrinology 158: 179-87.

[12.] Worda C, Leipold H, Gruber C, Kautzky-Willer A, Knofler M, et al. (2004) Decreased plasma adiponectin concentrations in women with gestational diabetes mellitus. American journal of obstetrics and gynecology 191: 2120-4.

[13.] Ntaios G, Gatselis NK, Makaritsis K, Dalekos GN (2013) Adipokines as mediators of endothelial function and atherosclerosis. Atherosclerosis 227: 216-21.

[14.] Adamczak M, Chudek J, Wiijcek A (2009) PROGRESS IN UREMIC TOXIN RESEARCH: Adiponectin in Patients with Chronic Kidney Disease. InSeminars in dialysis 22: 391-395.

[15.] Tong Q, Sankale JL, Hadigan CM, Tan G, Rosenberg ES, et al. (2003) Regulation of adiponectin in human immunodeficiency virus-infected patients: relationship to body composition and metabolic indices. The Journal of Clinical Endocrinology & Metabolism 88: 1559-64.

[16.] Lindegaard B, Keller P, Bruunsgaard H, Gerstoft J, Pedersen BK (2004) Low plasma level of adiponectin is associated with stavudine treatment and lipodystrophy in HIV-infected patients. Clinical & Experimental Immunology 135: 273-9.

[17.] Degenhardt L, Hall W (2012) Extent of illicit drug use and dependence, and their contribution to the global burden of disease. The Lancet 379: 55-70.

[18.] Mathers BM, Degenhardt L, Phillips B, Wiessing L, Hickman M, et al. (2008) Global epidemiology of injecting drug use and HIV among people who inject drugs: a systematic review. The Lancet 372: 1733-45.

[19.] Aceijas C, Stimson GV, Hickman M, Rhodes T (2004) Global overview of injecting drug use and HIV infection among injecting drug users. Aids 18: 2295-303.

[20.] Selwyn PA, Alcabes P, Hartel D, Buono D, Schoenbaum EE, et al. (1992) Clinical manifestations and predictors of disease progression in drug users with human immunodeficiency virus infection. New England Journal of Medicine 327: 1697-703.

[21.] Were T, Wesongah JO, Munde E, Ouma C, Kahiga TM, et al. (2014) Clinical chemistry profiles in injection heroin users from Coastal Region, Kenya. BMC clinical pathology 14: 1.

[22.] Meijerink H, Wisaksana R, Iskandar S, den Heijer M, van der Ven AJ, et al. (2014) Injecting drug use is associated with a more rapid CD4 cell decline among treatment naive HIV-positive patients in Indonesia. Journal of the International AIDS Society 17.

[23.] Shahouzehi B, Shokoohi M, Najafipour H (2013) The effect of opium addiction on serum adiponectin and leptin levels in male subjects: a case control study from kerman coronary artery disease risk factors study (KERCADRS). EXCLI Journal 12: 916.

[24.] Housova J, Wilczek H, Haluzik MM, Kremen J (2005) Adipocyte-derived hormones in heroin addicts: the influence of methadone maintenance treatment. Physiological Research 54: 73.

[25.] Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, et al. (2001) PPARy ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50: 2094-9.

[26.] Seo JB, Moon HM, Noh MJ, Lee YS, Jeong HW, et al. (2004) Adipocyte determination-and differentiation-dependent factor 1/sterol regulatory element-binding protein 1c regulates mouse adiponectin expression. Journal of biological chemistry 279: 22108-17.

[27.] Zuo Y, Qiang L, Farmer SR (2006) Activation of CCAAT/enhancer-binding protein (C/EBP) a expression by C/EBPp during adipogenesis requires a peroxisome proliferator-activated receptor-[gamma]-associated repression of HDAC1 at the C/ebpa gene promoter. Journal of biological chemistry 281: 7960-7.

[28.] Qiao L, MacLean PS, Schaack J, Orlicky DJ, Darimont C, et al. (2005) C/ EBPa regulates human adiponectin gene transcription through an intronic enhancer. Diabetes 54: 1744-54.

[29.] Kadowaki T, Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocrine reviews. 26: 439-51.

[30.] Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, et al. (2003) Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423: 762-9.

[31.] Bodles AM, Banga A, Rasouli N, Ono F, Kern PA, Owens RJ. Pioglitazone increases secretion of high-molecular-weight adiponectin from adipocytes. American Journal of Physiology-Endocrinology and Metabolism. 2006 Nov 1; 291 (5): E1100-5.

[32.] Yang WS, Jeng CY, Wu TJ, Tanaka S, Funahashi T, et al. (2002) Synthetic peroxisome proliferator-activated receptor-[gamma] agonist, rosiglitazone, increases plasma levels of adiponectin in type 2 diabetic patients. Diabetes care 25: 376-80.

[33.] Joseph GY, Javorschi S, Hevener AL, Kruszynska YT, Norman RA, et al. (2002) The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 51: 2968-74.

[34.] Wang Y, Lam KS, Yau MH, Xu A (2008) Post-translational modifications of adiponectin: mechanisms and functional implications. Biochemical Journal 409: 623-33.

[35.] Liu M, Liu F (2010) Transcriptional and post-translational regulation of adiponectin. Biochemical Journal 425: 41-52.

[36.] Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, et al. (2003) Structure-function studies of the adipocyte-secreted hormone Acrp30/ adiponectin implications for metabolic regulation and bioactivity. Journal of Biological Chemistry 278: 9073-85.

[37.] Simpson F, Whitehead JP (2010) Adiponectin--it's all about the modifications. The international journal of biochemistry & cell biology 42: 785-8.

[38.] Long Q, Lei T, Feng B, Yin C, Jin D, et al. (2010) Peroxisome proliferator-activated receptor-[gamma] increases adiponectin secretion via transcriptional repression of endoplasmic reticulum chaperone protein ERp44. Endocrinology 151: 3195-203.

[39.] Qiang L, Wang H, Farmer SR (2007) Adiponectin secretion is regulated by SIRT1 and the endoplasmic reticulum oxidoreductase Ero1-La. Molecular and cellular biology 27: 4698-707.

[40.] Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, et al. (2003) Impaired multimerization of human adiponectin mutants associated with diabetes molecular structure and multimer formation of adiponectin. Journal of Biological Chemistry 278: 40352-63.

[41.] Gable DR, Hurel SJ, Humphries SE (2006) Adiponectin and its gene variants as risk factors for insulin resistance, the metabolic syndrome and cardiovascular disease. Atherosclerosis 188: 231-44.

[42.] Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, et al. (2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. The Journal of clinical investigation 116: 1784-92.

[43.] Brochu-Gaudreau K, Rehfeldt C, Blouin R, Bordignon V, Murphy BD, et al. (2010) Adiponectin action from head to toe. Endocrine 37: 11-32.

[44.] Tsao TS, Tomas E, Murrey HE, Hug C, Lee DH, et al. (2003) Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity different oligomers activate different signal transduction pathways. Journal of Biological Chemistry 278: 50810-7.

[45.] Wang Y, Lam KS, Xu JY, Lu G, Xu LY, et al. (2005) Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner. Journal of Biological Chemistry 280: 18341-7.

[46.] Kadowaki T, Yamauchi T (2005) Adiponectin and adiponectin receptors. Endocrine reviews 26: 439-51.

[47.] Sweeney G (2011) Adiponectin action: a combination of endocrine and autocrine/paracrine effects. Frontiers in endocrinology 2: 62.

[48.] Ukkola O, Santaniemi M (2002) Adiponectin: a link between excess adiposity and associated comorbidities?. Journal of molecular medicine 80: 696-702.

[49.] Arita Y (2012) Reprint of paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochemical and biophysical research communications 425: 560-4.

[50.] Wajchenberg BL, Giannella-Neto D, Da Silva ME, Santos RF (2002) Depot-specific hormonal characteristics of subcutaneous and visceral adipose tissue and their relation to the metabolic syndrome. Hormone and metabolic research 34: 616-21.

[51.] Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, et al. (2001) Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proceedings of the National Academy of Sciences 98: 2005-10.

[52.] Berg AH, Combs TP, Scherer PE (2002) ACRP30/adiponectin: an adipokine regulating glucose and lipid metabolism. Trends in Endocrinology & Metabolism 13: 84-9.

[53.] Adamczak M, Wiecek A (2013) The adipose tissue as an endocrine organ. Seminars in Nephrology, WB Saunders.

[54.] Kappes A, Loffler G (2000) Influences of ionomycin, dibutyryl-cyclo-AMP and tumour necrosis factor-alpha on intracellular amount and secretion of apM1 in differentiating primary human preadipocytes. Hormone and Metabolic Research 32: 548-54.

[55.] Ouchi N, Kihara S, Funahashi T, Matsuzawa Y, Walsh K (2003) Obesity, adiponectin and vascular inflammatory disease. Current opinion in lipidology 14: 561-6.

[56.] Takemura Y, Ouchi N, Shibata R, Aprahamian T, Kirber MT, et al. (2007) Adiponectin modulates inflammatory reactions via calreticulin receptor--dependent clearance of early apoptotic bodies. The Journal of clinical investigation 117: 375-86.

[57.] Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, et al. (2000) Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-kB signaling through a cAMP-dependent pathway. Circulation 102: 1296-301.

[58.] Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, et al. (2000) Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96: 1723-32.

[59.] Hotamisligil GS (1999) Mechanisms of TNF-[alpha]-induced insulin resistance. Experimental and clinical endocrinology & diabetes 107: 119-25.

[60.] Tian L, Luo N, Klein RL, Chung BH, Garvey WT, et al. (2009) Adiponectin reduces lipid accumulation in macrophage foam cells. Atherosclerosis 202: 152-61.

[61.] Tian L, Luo N, Zhu X, Chung BH, Garvey WT, et al. (2012) Adiponectin-AdipoR1/2-APPL1 signaling axis suppresses human foam cell formation: differential ability of AdipoR1 and AdipoR2 to regulate inflammatory cytokine responses. Atherosclerosis 221: 66-75.

[62.] Kubota N, Terauchi Y, Yamauchi T, Kubota T, Moroi M, et al. (2002) Disruption of adiponectin causes insulin resistance and neointimal formation. Journal of Biological Chemistry 277: 25863-6.

[63.] Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, et al. (2001) The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature medicine 7: 941-6.

[64.] Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L (2001) Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. The Journal of clinical investigation 108: 1875-81.

[65.] Berg AH, Combs TP, Du X, Brownlee M, Scherer PE (2001) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nature medicine 7: 947-53.

[66.] Almeida M, Cordero M, Almeida J, Orfao A (2005) Different subsets of peripheral blood dendritic cells show distinct phenotypic and functional abnormalities in HIV-1 infection. Aids 19: 261-71.

[67.] Hruz PW (2006) Molecular mechanisms for altered glucose homeostasis in HIV infection. American journal of infectious diseases 2: 187.

[68.] Tong Q, Sankale JL, Hadigan CM, Tan G, Rosenberg ES, et al. (2003) Regulation of adiponectin in human immunodeficiency virus-infected patients: relationship to body composition and metabolic indices. The Journal of Clinical Endocrinology & Metabolism 88: 1559-64.

[69.] Kosmiski L, Kuritzkes D, Lichtenstein K, Eckel R (2003) Adipocyte-derived hormone levels in HIV lipodystrophy. Antiviral therapy 8: 9-16.

[70.] Sankale JL, Tong Q, Hadigan CM, Tan G, Grinspoon SK, et al. (2006) Regulation of adiponectin in adipocytes upon exposure to HIV-1. HIV medicine 7: 268-74.

[71.] Hamdy O, Porramatikul S, Al-Ozairi E (2006) Metabolic obesity: the paradox between visceral and subcutaneous fat. Current diabetes reviews 2: 367-73.

[72.] Fiorenza CG, Chou SH, Mantzoros CS (2011) Lipodystrophy: pathophysiology and advances in treatment. Nature Reviews Endocrinology 7: 137-50.

[73.] Addy CL, Gavrila A, Tsiodras S, Brodovicz K, Karchmer AW, et al. (2003) Hypoadiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat redistribution in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy. The Journal of Clinical Endocrinology & Metabolism 88: 627-36.

[74.] Kosmiski LA, Bacchetti P, Kotler DP, Heymsfield SB, Lewis CE, et al. (2008) Relationship of fat distribution with adipokines in human immunodeficiency virus infection. The Journal of Clinical Endocrinology & Metabolism 93: 216-24.

[75.] Carr A (2003) HIV lipodystrophy: risk factors, pathogenesis, diagnosis and management. Aids 17: S141-8.

[76.] de Luis DA, Bachiller P, Palacios T, Conde R, Izaola O, et al. (2012) Relationship of fat distribution with adipokines in patients with acquired immunodeficiency virus infection. Journal of clinical laboratory analysis 26: 336-41.

[77.] de Waal R, Cohen K, Maartens G (2013) Systematic review of antiretroviral-associated lipodystrophy: lipoatrophy, but not central fat gain, is an antiretroviral adverse drug reaction. PloS one 8: e63623.

[78.] de la Concepcion MR, Yubero P, Domingo JC, Iglesias R, Domingo P, et al. (2005) Reverse transcriptase inhibitors alter uncoupling protein-1 and mitochondrial biogenesis in brown adipocytes. Antiviral therapy 10: 515-26.

[79.] Moure R, Domingo P, Gallego-Escuredo JM, Villarroya J, del Mar Gutierrez M, et al. (2016) Impact of elvitegravir on human adipocytes: Alterations in differentiation, gene expression and release of adipokines and cytokines. Antiviral research 132: 59-65.

[80.] M Gallego-Escuredo J, del Mar Gutierrez M, Diaz-Delfin J, C Domingo J, Gracia Mateo M, et al. (2010) Differential effects of efavirenz and lopinavir/ritonavir on human adipocyte differentiation, gene expression and release of adipokines and pro-inflammatory cytokines. Current HIV research 8: 545-53.

[81.] Diaz-Delfin J, Domingo P, Mateo MG, del Mar Gutierrez M, Domingo JC, et al. (2012) Effects of rilpivirine on human adipocyte differentiation, gene expression, and release of adipokines and cytokines. Antimicrobial agents and chemotherapy 56: 3369-75.

[82.] Diaz-Delfin J, del Mar Gutierrez M, Gallego-Escuredo JM, Domingo JC, Mateo MG, et al. (2011) Effects of nevirapine and efavirenz on human adipocyte differentiation, gene expression, and release of adipokines and cytokines. Antiviral research 91: 112-9.

[83.] Diaz-Delfin J, Domingo P, Giralt M, Villarroya F (2013) Maraviroc reduces cytokine expression and secretion in human adipose cells without altering adipogenic differentiation. Cytokine 61: 808-15.

[84.] Yamamoto Y, Hirose H, Saito I, Tomita M, Taniyama M, et al. (2002) Correlation of the adipocyte-derived protein adiponectin with insulin resistance index and serum high-density lipoprotein-cholesterol, independent of body mass index, in the Japanese population. Clinical Science 103: 137-42.

[85.] Dekker JM, Funahashi T, Nijpels G, Pilz S, Stehouwer CD, et al. (2008) Prognostic value of adiponectin for cardiovascular disease and mortality. The Journal of Clinical Endocrinology & Metabolism 93: 1489-96.

[86.] Lucas GM, Gebo KA, Chaisson RE, Moore RD (2002) Longitudinal assessment of the effects of drug and alcohol abuse on HIV-1 treatment outcomes in an urban clinic. Aids 16: 767-74.

[87.] Finley MJ, Happel CM, Kaminsky DE, Rogers TJ (2008) Opioid and nociceptin receptors regulate cytokine and cytokine receptor expression. Cellular immunology 252: 146-54.

[88.] Weiss L, Zeira M, Reich S, Har-Noy M, Mechoulam R, et al. (2006) Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity 39:143-51.

[89.] Daimon M, Oizumi T, Saitoh T, Kameda W, Hirata A, et al. (2003) Decreased serum levels of adiponectin are a risk factor for the progression to type 2 diabetes in the Japanese Population The Funagata study. Diabetes care 26: 2015-20.

[90.] Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, et al. (2001) Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50: 1126-33.

[91.] Yamauchi T, Kamon J, Minokoshi YA, Ito Y, Waki H, et al. (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nature medicine 8: 1288-95.

[92.] Hirose H, Kawai T, Yamamoto Y, Taniyama M, Tomita M, et al. (2002) Effects of pioglitazone on metabolic parameters, body fat distribution, and serum adiponectin levels in Japanese male patients with type 2 diabetes. Metabolism 51: 314-7.

[93.] Tsuchida A, Yamauchi T, Kadowaki T (2005) Nuclear Receptors as Targets for Drug Development: Molecular Mechanisms for Regulation of Obesity and Insulin Resistance by Peroxisome Proliferator-Activated Receptor. GAMMA., CREB-Binding Protein, and Adiponectin. Journal of pharmacological sciences 97: 164-70.

[94.] Phillips SA, Ciaraldi TP, Oh DK, Savu MK, Henry RR (2008) Adiponectin secretion and response to pioglitazone is depot dependent in cultured human adipose tissue. American Journal of Physiology-Endocrinology and Metabolism 295: E842-50.

[95.] Liu Y, Chewchuk S, Lavigne C, Brule S, Pilon G, et al. (2009) Functional significance of skeletal muscle adiponectin production, changes in animal models of obesity and diabetes, and regulation by rosiglitazone treatment. American Journal of Physiology-Endocrinology and Metabolism 297: E657-64.

[96.] Saito K, Tobe T, Yoda M, Nakano Y, Choi-Miura NH, et al. (1999) Regulation of gelatin-binding protein 28 (GBP28) gene expression by C/ EBP. Biological and Pharmaceutical Bulletin 22: 1158-62.

Nathan G Kiboi (1) *, Joseph K Karanja (2) and Saraphine N Nebere (1)

(1) Department of Biochemistry and Biotechnology, School of Pure and Applied Sciences, Kenyatta University, P. O BOX 43844-00100, Nairobi, Kenya

(2) Department of Zoological Sciences, School of Pure and Applied Sciences, Kenyatta University, P.O BOX 43844-00100, Nairobi, Kenya

* Corresponding author: Nathan G Kiboi, Department of Biochemistry and Biotechnology, School of Pure and Applied Sciences, Kenyatta University, Nairobi, Kenya, Tel: +254718145100; E-mail:

Received date: July 05, 2016; Accepted date: July 20, 2016; Published date: July 27, 2016

Table 1: Classification of various ART regimens and their effects on
Acrp30 production/levels.

Drug    Class   Effect on      Proposed Mechanism of effect    Author

d4T     NRTI    [down arrow]   Drug-induced mitochondrial      [16]
                                 dysfunction in adipocytes
EVG     InSTI   [down arrow]   Alters adipocyte                [79]
                                 differenciation and
RPV     RPV     [down arrow]   Represses adipocyte             [81]
                                 differentiation causing
                                 impaired expression of
                                 main adipogenesis
                                 regulators including;
                                 PPAR-[gamma], SREBP-1
                                 and C/EBP-[alpha].
NVP     NNRTI   [up arrow]     Fails to impede adipogenesis    [82]
                                 but heightens expression
                                 of adipose regulators of
                                 SREBP-1, C/EBP-[alpha]
                                 and PPAR-[gamma].
EFV     NNRTI   [down arrow]   Disrupts human adipogenesis     [78]
                                 by down-regulating
                                 expression of associated
                                 marker genes including;
                                 FABP-4, PPAR-[gamma] and
                                 C/ EBP-[alpha].
LPV/r   PI's    [down arrow]   Impairs adipocyte               [80]
                                 differentiation while
                                 reducing transcript levels
                                 of adipogenesis
                                 regulators comprising
                                 PPAR-[gamma] and
MVC     FI's    None           Does not alter adipogenic       [83]
                                 differentiation in human
                                 adipose cells.

Note: NRTI: Nucleoside Reverse Transcriptase inhibitor; NNRTI:
Non-Nucleoside Reverse Transcriptase inhibitor; InSTI: Integrase
Strand Transfer Inhibitor; PI's: Protease Inhibitors; ART:
Antiretroviral Therapy; d4T: Stavudine; EVG: Elvitegravir;
RPV: Rilpivirine; NVP: Nevirapine; EFV: Efavirenz; LPV/r:
Lopinavir/ritonavir; PPAR-[gamma]: Peroxisome-Proliferator
Activated Receptor gamma; SREBP-1: Sterol Regulatory Element
Binding Protein-1; C/EBP-[alpha]: CCAAT Enhancer Binding
Protein alpha; FABP-4: Fatty Acid Binding Protein 4.
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Author:Kiboi, Nathan G.; Karanja, Joseph K.; Nebere, Saraphine N.
Publication:Biology and Medicine
Article Type:Report
Date:Nov 1, 2016
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