ArticlePDF Available

Metadichol ® A Novel Nano Lipid; GPR 120 Agonist


Abstract and Figures

Metadichol® is a Nanoemulsion of long-chain alcohols found in many foods. Metadichol acts as an inverse agonist on Nuclear Vitamin D receptors (VDR) that have a ubiquitous presence in cells and acts by modulating the immune system and affects many biological processes to modulate many diseases. We have demonstrated that Metadichol is useful in both type 1 and two diabetes and in modulating insulin levels and reducing sugar levels and thus increasing insulin sensitivity. We had earlier shown that it binds to VDR and thus an effect on glucose homeostasis that is a hallmark of VDR pathways. We now report also that it is an agonist of GPR120 (G protein-coupled receptor 120) which has emerged as a key target for metabolic diseases like obesity and insulin resistance. In the in-vitro assay, Metadichol is comparable to GW9508 the most extensively used standard compound in GPR 120 research.
Content may be subject to copyright.
Volume 1 | Issue 1 | 1 of 4
Int J Diabetes Complications, 2017
Metadichol ® A Novel Nano Lipid; GPR 120 Agonist
Research Article
Nanorx Inc, PO Box 131, Chappaqua, NY 10514, US
PR Raghavan, Founder and CEO, Nanorx Inc, Chappaqua, NY,
USA, Tel: (914) 671-0224; E-mail:
Received: 15 Apr 2017; Accepted: 02 May 2017
Raghavan P.R
International Journal of Diabetes & its Complications
Metadichol® is a Nanoemulsion of long-chain alcohols found in many foods. Metadichol acts as an inverse ag-
onist on Nuclear Vitamin D receptors (VDR) that have a ubiquitous presence in cells and acts by modulating the
immune system and affects many biological processes to modulate many diseases.
We have demonstrated that Metadichol is useful in both type 1 and two diabetes and in modulating insulin levels
and reducing sugar levels and thus increasing insulin sensitivity. We had earlier shown that it binds to VDR and
thus an effect on glucose homeostasis that is a hallmark of VDR pathways. We now report also that it is an
agonist of GPR120 (G protein-coupled receptor 120) which has emerged as a key target for metabolic diseases
like obesity and insulin resistance.
In the in-vitro assay, Metadichol is comparable to GW9508 the most extensively used standard compound in GPR
120 research.
Research Article
Citation: Raghavan P.R. Metadichol® A Novel Nano Lipid; GPR 120 Agonist. Int J Diabetes Complications. 2017; 1-3.
Metadichol, VDR, Nuclear receptors, Inverse agonists, Protean
agonists, GPR 120, FFAR4, Lipids, Insulin Resistance, Insulin
sensitivity, Type 1 and Type 2 diabetes, Network biology, Multiple
receptors targeting, BCAT1, PPARG.
Diabetes is rampant across the world and was the cause of 4.6
million deaths in 2011. By the year 2030, over 450 million people
will be affected [1].
Lifestyle disease modication like diet control can help in
preventing Type two diabetes. Many experimental drugs are in
various phases of development, but despite new insights into the
mechanism of the disease, as of today, no effective solution is in
Increasingly research has been that focussed on the superfamily
of GPCRs and there are over 800, seven-transmembrane receptors
that display different physiological and pathological functions [2].
Free fatty acids (FFAs) are known to act in regulating physiological
functions through G-protein-coupled receptors the most important
being GPR-120, also known as FFAR4, which is now an important
therapeutic target against diabetes [3].
GPR120 have a ubiquitous presence in various tissues and cells
[4]. GPR120 has functions in the homeostatic regulation of
systemic metabolism and inammation depending on this different
tissue distribution. GPR120 activation can lead to positive effects
on type 2 diabetes. GPR120 signals via both β- arrestin 2 and G
proteins in the reported studies. GPR120 is an emerging target in
the eld of metabolic diseases.
The GPCR assay was carried out by DiscoverRX, CA USA
using PathHunter® assays which use adapted β-galactosidase
complementation system. Enzyme Fragment Complementation
(EFC) with β-galactosidase (β-Gal) as the functional reporter. In
the PathHunter® β-Arrestin assay. The GPCR assays are the whole
cell, functional tests that directly measure activity by detecting the
interaction of β-Arrestin with the activated GPCR. It monitors the
activation of a GPCR in a homogenous, non-imaging assay format.
The enzyme is split into two inactive complementary portions: a
small peptide called ProLink™ (PK) and a larger protein, called
Enzyme Acceptor (EA). PK and EA are then expressed as fusion
proteins in the cell, with PK fused to the GPCR of in-terest, and
Volume 1 | Issue 1 | 2 of 4Int J Diabetes Complications, 2017
EA fused to β-Arrestin. When the target GPCR is activated, and
β-Arrestin recruited to the receptor, PK, and EA complementation
occurs, restoring β-Galactosidase activity which is measured using
chemilumi-nescent PathHunter® Detection Reagents. GW9508, a
known GPR 120 agonist, was used as the standard.
Cell Handling
PathHunter® cell lines were thawed from freezer stocks
according to standard procedures.
Cells were seeded in a total volume of 20 μL into white-
walled, 384-well microplates and incubated at 37°C for a
stipulated time before testing.
Agonist Format
For agonist determination, cells were incubated with the
sample to induce the response.
Intermediate dilution of samples was carried out to obtain the
5X samples required in assay buffer
ve μL of 5X sample was added to cells and incubated at 37°C
or room temperature for 90 or 180 minutes. Fi-nal test vehicle
concentration was 1%.
Signal Detection
Assay signal generated through a single addition of 12.5 or 15
μL (50% v/v) of PathHunter agent for detection followed by
one-hour incubation at room temperature.
Microplates were then read following signal generation with a
Perkin Elmer EnvisionTM instrument for chemi-luminescent
signal detection.
Data Analysis
Compound activity was analyzed using CBIS data analysis
suite (ChemInnovation, CA).
For agonist mode assays, percentage activity was calculated
using as follows;
% Activity =100% x (mean RLU of test sample — mean RLU of
vehicle control) / (mean MAX control ligand — mean RLU of
vehicle control).
Agonist assays, data was normalized to the maximal and minimal
response observed in the presence of control ligand and vehicle.
Summary of Results
Table 1 shows the summary of results. Table 2 and 2-1 show the
raw data, and Figure 1 shows the graphs of the agonist activity.
Metadichol has the same response as the known GPR120 agonist
Table 1
EC50 (ug/
Curve Top
Metadichol Arrestin Agonist GPR120 3.3141 1.48 -4.1 105 105.3
GW9508 Arrestin Agonist GPR120 3.478 1.03 -5.5 105 101.68
Table 2
Well ID Concentration Raw Value Percent Efcacy
E21 0.048828 16800 -6.3995
E22 0.048828 16000 -8.468
E19 0.097656 17000 -5.8824
E20 0.097656 17600 -4.331
E17 0.19531 16800 -6.3995
E18 0.19531 17000 -5.8824
E15 0.39063 21000 4.4602
E16 0.39063 19000 -0.71105
E13 0.78125 23000 9.6315
E14 0.78125 22800 9.1144
E11 1.5625 29800 27.214
E12 1.5625 27600 21.526
E9 3.125 38200 48.933
E10 3.125 36800 45.314
E7 6.25 48000 74.273
E8 6.25 45000 66.516
E5 12.5 56200 95.475
E6 12.5 55400 93.407
E3 25 62000 110.47
E4 25 58000 100.13
Well ID Concentration Raw Value Percent Efcacy
A21 0.0050805 16200 -7.9509
A22 0.0050805 18400 -2.2624
A19 0.015242 16000 -8.468
A20 0.015242 16600 -6.9166
A17 0.045725 17000 -5.8824
A18 0.045725 18800 -1.2282
A15 0.13717 18800 -1.2282
A16 0.13717 18200 -2.7796
A13 0.41152 22600 8.5973
A14 0.41152 21200 4.9774
A11 1.2346 27400 21.008
A12 1.2346 27800 22.043
A9 3.7037 40800 55.656
A10 3.7037 39000 51.002
A7 11.111 49400 77.893
A8 11.111 48000 74.273
A5 33.333 55600 93.924
A6 33.333 59000 102.71
A3 100 61000 107.89
A4 100 56200 95.475
Metadichol ® is a Nanoemulsion in water and has a particle size of
less than 60 nm. Its mechanism of action is through its binding to
the vitamin D receptor (VDR) as an inverse agonist [5].
The natural ligand for the VDR is 1,25-Dihydroxy Vitamin D is
and acts as an agonist. Metadichol can act as both positive or as
Volume 1 | Issue 1 | 3 of 4Int J Diabetes Complications, 2017
negative agonists on the same receptor a property characteristic
of protean agonist [6,7]. In the absence of constitutive activity,
it behaves as an active agonist. If constitutive activity is present,
it acts as an inverse agonist. Metadichol can reduce or increase
insulin secretion [5,8].
For the functioning of the skeletal system [9], Vitamin D is very
critical for the regulation of the immune system [9]. It has a vital
role not only in controlling insulin synthesis and secretion as well
[10,11]. Metadichol in addi-tion to binding with VDR also binds to
other nuclear receptors that include PPAR Gamma [12].
Flawed metabolism of Branched Chain Amino Acid (BCAA) is
associated with many chronic conditions like type II diabetes and
other childhood disorders [13]. Metformin has been shown to in-
hibit expression of mitochondrial branched-chain aminotransfer-
ase (BCAT) [14]. We have recently shown that Metadichol is a
potent inhibitor of BCAT1 [15].
The Agonism exhibited by Metadichol in GPR 120 assays show
that it is acting on more than one target, VDR, BCAT1, has been
shown previously. The current research approach that of a lock
(receptor) and key (drug). The search to mitigate the side effects
of drugs by looking for high selective ligands and has proven to
be cost and time consuming without any in many ways a failure.
Useful drugs act via pathways in targeting multiple proteins
rather than single targets. Protein kinase inhibitors like Sutent and
Gleevec, have demonstrated that their anticancer actions are due to
their effects on multiple kinases [16].
Yıldırım, M.A, suggest that there are many keys open a lock
but the goal of drug discovery is to have a single key to open many
locks, i.e., act via multiple pathways [17]. A practical approach
for mitigating disease states may require multiple activities to be
efcacious, together with the observation that perturbs biological
networks is more important than individual targets [18].
Previously we have published case studies of Metadichol ® in
Type 1 diabetes and type 2 diabetes patients [8,19]. It appears
to be more efcient than many drugs on the market as it works
multiple pathways on multiple receptor targets. Metadichol acts
at the nuclear receptor level (VDR) and the transmembrane level
(GPR120) and the Cytoplasm and mitochondrial level (inhibition
of BCAT1) is probably what makes it such a powerful treatment of
choice in diabetes relate diseases.
Metadichol has the potential to serve in mitigating diabetes
with a broad spectrum of activity and with a safety with no
toxicity at doses of up to 5000 mg/kg [20-22]. Metadichol is a
a far effective substitute to prescription drugs, which have been
largely ineffective in diabetes and have many side effects that add
to health care costs.
1. Zimmet P, Alberti KG, Shaw J. Global and societal implications
of the diabetes epidemic. Nature Dec. 2001; (6865): 782-787.
2. Tang XL. Orphan G protein-coupled receptors (GPCRs):
biological functions and potential drug targets. Acta Pharmacol
Sin. 2012; 33: 363-371.
3. Cornall LM. GPR120 agonist as the countermeasure against
metabolic diseases. Drug Discov Today. 2013; 19: 670-679.
4. Oh DY. GPR120 is an omega-3 fatty acid receptor mediating
potent anti-inammatory and insulin-sensitizing effects. Cell.
2010; 42: 687-698.
5. P.R. Raghavan. US patents, 8,722,093 (2014) and 9,006,292.
6. Terry Kenakin. Functional Selectivity through Protean and
Biased Agonism: Who Steers the Ship? Mol Phar-macol.
2007; 72: 1393-1402.
7. Neubig RR. Missing Links, Mechanisms of Protean Agonism,
Mol Pharmacol. 2000; l71: 200-1202.
8. P.R. Raghavan. A case report of Type 1 Diabetes. Journal of
the Science of Healing Outcomes. 2010; 2: 8-9.
9. Christakos S, Hewison M, Gardner DG, et al. Vitamin D:
Beyond Bone. Ann N Y Acad Sci. 2013; 1287: 45-58.
Volume 1 | Issue 1 | 4 of 4Int J Diabetes Complications, 2017
© 2017 Raghavan P.R. is article is distributed under the terms of the Creative Commons Attribution 4.0 International License
10. Bikle DD. Vitamin D and immune function: Understanding
common pathways. Curr Osteo-poros Rep 2009; 7: 58-63.
11. Palmer X, González-Clemente JM, Blanco-Vaca F, et al. Role
of vitamin D in the pathogene-sis of type 2 diabetes mellitus.
Diabetes Obes Metab. 2008; 10: 185-197.
12. Raghavan PR. Unpublished work.
13. Skvorak KJ. Animal models of maple syrup urine disease. J
Inherit Metab Dis. 2009; 32: 229-246.
14. Davis S. Sonnet. Metformin inhibits Branched Chain Amino
Acid (BCAA) derived ketoaci-dosis and promotes metabolic
homeostasis in MSUD. Nature Scientic Reports. 2006; 6:
15. P.R. Raghavan, 2017; Improving Longevity with Metadichol
® by inhibiting Bcat-1 Gene. Journal of Aging Science. 5:1,
DOI: 10.4172/2329-8847.1000174
16. Roth BL, Shefer DJ, Kroeze WK, et al. Nat Rev Drug
Discov. 2004; 3: 353-359.
17. Yildırım MA. Drug-target network. Nat Biotechnol. 2007; 25:
18. Andrew Hopkins. Network pharmacology: the next paradigm
in drug discovery. Nature Chemical Biology. 2007; 4: 11.
19. PR Raghavan. Metadichol and Type 2 Diabetes A case report.
Journal of the Science of Healing Outcomes: 2016; 32: 5-10.
20. Alemán CL, Más R, Hernández, et al. A 12-month study of
policosanol oral toxicity in Spra-gue Dawley rats. Toxicol
Lett. 1994; 70: 77-87.
21. Alemán, CL, Más Ferreiro. Carcinogenicity of policosanol in
Sprague-Dawley rats: A 24-month study. Teratog Carcinog
Mutagen. 1994; 14: 239-249.
22. Aleman, CL, Puig MN, EIN, EC, et al. Carcinogenicity of
policosanol in mice: An 18-month study. 1995.
View publication statsView publication stats
... Diseases are connected through closely related gene networks, and this is an approach that can be exploited to modulate multiple targets to enhance therapeutic effect as ligands today are focused on a single target and limited by their efficacy. Metadichol is a safe therapeutic that target multiple genes, pathways and multiple diseases that confirms the relevance of network-based approach of polypharmacology [77] and this has been demonstrated by our studies on other diseases [78][79][80][81][82][83][84][85][86][87][88][89][90][91]. ...
Full-text available
Liver diseases are becoming a major health concern. In the developing countries it is due to microbial infection. In the rest of the developed world it is due to alcohol abuse. Chronic liver disease and cirrhosis are a significant health concern in western countries. It is the fifth most common cause of death, after heart disease, cancer, stroke, and chest disease. The liver is capable of regeneration, but it can be overwhelmed leading to liver diseases like cirrhosis and hepatocellular cancer (HCC). Vitamin D levels are low in most patients with liver diseases, and this suggests possible therapeutic benefits with use of vitamin D or its analogues. Vitamin D, through the vitamin D nuclear receptor (VDR) plays a crucial role in mineral ion homeostasis. The liver has a central role in vitamin D synthesis and there is a need for an agent that will not lead to hypercalcemia. Metadichol, a nano emulsion of long-chain alcohols derived from food, is an inverse agonist of Vitamin D can fill this void. In Diabetic rat studies, it inhibits TNF alpha, ICAM1 (intracellular adhesion molecule), CCL2 (chemokine CC motif) also referred to as monocyte chemoattractant protein 1 (MCP1). All these cytokines, chemokines are known to have important role in liver diseases. We show that Metadichol indeed does work in liver disease patients by normalizing essential liver enzymes ALT, AST and ALP, and GGT. This approach is an example where Metadichol targets multiple genes and via multiple pathways to bring about homeostasis of the liver and is a useful, safe, non-toxic product in treating liver diseases and alleviating a global threat.
... This paper deals with Metadichol ® expression on UCB cells leading to increased CD33 expression similar to what we saw in CD34 expression. The increased expression observed with CD33 could be one possible mechanism that could explain its diverse pharmacological actions of Metadochol ® on multiple diseases [25][26][27][28][29][30][31][32][33][34][35][36][37][38]. ...
Full-text available
CD33 also known as Siglec-3 is endogenously expressed in stem cells and is a marker for the myeloid lineage of cells. Increased expression of CD33 thus allows it to bind to any Sialic Acids (SIAs). These acids are binding sites for pathogens and toxins. By binding to these acids, CD33 can prevent invasion of hosts by these pathogens. Down-regulation of CD33, increase the release of the pro-inflammatory cytokine TNF-α by monocytes that increases reactive oxygen species that are involved in diseases like diabetes mellitus, Alzheimer's, cardiovascular diseases asthma, and in various cancers. The up-regulation of CD33 using Metadichol ® was studied using Wharton's Jelly Mesenchymal Stem Cells (MSCs) isolated from human umbilical cord and were grown in p-35 dishes until confluent and treatment was carried out with different concentrations. One dish was untreated and considered as control. The treated and untreated cells were analyzed using Flow Cytometry. The cells treated at 100 pg of Metadichol ® has shown the highest increase (>400 fold) in CD33++ expression (48.77%) compared to untreated control (0.11%).
... Vitamin D3 role in innate immunity is to enable keratinocytes to recognize and respond to bacteria and to protect wounds against infection [31] Metadichol as we documented earlier has a powerful effect on diabetic patients [32,33]. Metadichol is an agonist of GPR 120 [34]. This is another pathway though which it can act as shown by Arantes El et al. [35] that the topical use of GPR 120 agonists like polyunsaturated fatty acids (PUFAs) can accelerate skin wound healing. ...
... The network-based approach is commonly called poly pharmacology [41]. Metadichol represents the first of a class of safe therapeutics that targets multiple pathways and multiple diseases that confirms the importance of network pharmacology [42][43][44][45][46][47][48][49][50][51][52][53]. ...
Full-text available
Psoriasis affects 3% of the population worldwide, and there is no known cure. Psoriasis is associated with an increased risk of psoriatic arthritis, lymphomas, cardiovascular disease, and Crohn’s disease. Psoriasis treatments today include steroid and vitamin D3 cream, ultraviolet light, and immune systemsuppressing medications such as methotrexate. The T cells responsible for psoriasis are Th1 and Th l7 cells. IL-22, produced by Th17 cells, is crucial for the proliferation of keratinocytes. IL-22 with the help of IL-17 can induce the critical events of psoriasis. To maintain Th17 cells, IL-23 is required, and it is released from tumor necrosis factor-alpha (TNF-alpha) induced pathways. The pathophysiology of psoriasis involves RORC (retinoic acid receptor-related orphan nuclear receptor gamma) as a critical transcription factor for the development of Th17 cells. FDA has approved an antibody Secukinumab® targeting TNF-α for the treatment of psoriasis. Other FDA approved drugs are Tremfya® targeting IL23 for treatment of moderate to severe plaque psoriasis and Taltz® that blocks IL17 for treatment of plaque psoriasis. Metadichol® a nanoformulation of long-chain lipid alcohols derived from food is a TNF-alpha inhibitor and also binds to Vitamin D receptor (VDR) that could have beneficial effects on Psoriasis. VDR modulates Th1-mediated inflammatory disease like psoriasis. We now present evidence that Metadichol is an inverse agonist of RORγt and AHR (Aryl Hydrocarbon Receptor) thus controlling Th17, IL17 and IL22. Being a TNF-alpha inhibitor, it can control IL23 thus blocking the significant pathways that exacerbate psoriasis. We present case studies of 7 patients afflicted with psoriasis and skin related conditions and how treatment with Metadichol resolved the underlying disease. Metadichol® has properties that allow its use as a safe nontoxic solution to combating the growing number of psoriasis cases
... Metadichol is a TNF-alpha inhibitor and also it binds to VDR, and hence it could be working through more than one pathway in modulating RDW and normalizing RBC and Hemoglobin levels. We have previously shown how Metadichol works on other diseases through the Vitamin D receptor as an inverse/protean agonist and other nuclear receptors (34)(35)(36)(37)(38)(39)(40)(41)(42). The results of this study demonstrate that Metadichol is safe and effective as evidenced by the improvement of various biomarkers such as RDW that lead to improved RBC and Hemoglobin levels in CKD patients. ...
Full-text available
Red blood cells originate in the bone marrow. Red cell distribution width (RDW) show sizes of circulating erythrocytes (RBC) and has been explored in several large clinical databases to be a robust marker of adverse clinical outcomes in patients. The prognostic value of RDW is seen in other conditions with end-organ dysfunction such as renal failure or. Elevated RDW levels are of significance in diseases such as kidney diseases. The high RDW levels are an indication of increased oxidative stress and closely related to the presence and poor prognosis of the disease. No known therapy exists that can normalize RDW levels. In this paper, we present here case studies using Metadichol® [1] that leads to normal RDW levels in patients with CKD and PKD.
Full-text available
Metadichol ® [1] is a Nanoemulsion of long-chain alcohols found in many foods. It is commonly called Policosanol and is present in foods such as rice, sugar cane, wheat, peanuts Metadichol acts as an inverse agonist on Nuclear Vitamin D receptors (VDR) that are present in cells throughout the body to stimulate the immune system and affects many biologIcal processes to modulate many diseases. Branched-chain amino acid transferase (BCAT1) catalyzes the reversible transamination of leucine, isoleucine, and valine branched-chain amino acids (BCAA) to their respective alpha-keto acids, liberating L-glutamate. When this gene is inhibited, the amino acid chains accumulated in the tissue triggering longevity in the nematodes. The health and longevity of the nematodes improved when BCAT1 was inhibited. Gabapentin has been shown to inhibit BCAT1, but IC50 is 10000 uM. Metadichol® inhibits BCAT1 with an IC50 of 3.3 um, 3000 times more potent than Gabapentin.
Full-text available
Maple Syrup Urine Disease (MSUD) is an inherited disorder caused by the dysfunction in the branched chain keto-acid dehydrogenase (BCKDH) enzyme. This leads to buildup of branched-chain keto-acids (BCKA) and branched-chain amino acids (BCAA) in body fluids (e.g. keto-isocaproic acid from the BCAA leucine), leading to numerous clinical features including a less understood skeletal muscle dysfunction in patients. KIC is an inhibitor of mitochondrial function at disease relevant concentrations. A murine model of intermediate MSUD (iMSUD) shows significant skeletal muscle dysfunction as by judged decreased muscle fiber diameter. MSUD is an orphan disease with a need for novel drug interventions. Here using a 96-well plate (liquid chromatography- mass spectrometry (LC-MS) based drug-screening platform we show that Metformin, a widely used anti-diabetic drug, reduces levels of KIC in patient-derived fibroblasts by 20–50%. This Metformin-mediated effect was conserved in vivo; Metformin-treatment significantly reduced levels of KIC in the muscle (by 69%) and serum (by 56%) isolated from iMSUD mice, and restored levels of mitochondrial metabolites (e.g. AMP and other TCA). The drug also decreased the expression of mitochondrial branched chain amino transferase (BCAT) which produces KIC in skeletal muscle. This suggests that Metformin can restore skeletal muscle homeostasis in MSUD by decreasing mitochondrial KIC production.
Full-text available
Background Metadichol (1,2) is a Nano emulsion of long-chain alcohols called policosanols which are found in many foods like rice, wheat, grapes, sugar cane, apple and many others (3). It acts on membrane receptors in cells throughout the body to stimulate the immune system and inhibit a variety of disease processes, including those that result in metabolic diseases such as diabetes, obesity and hypertension. Methods A 38-year-old male of middle eastern origin was diagnosed as diabetic after complaining of tiredness and bouts of hunger. He was not on any medication and chose to be treated with Metadichol @ 10 mg per day. Findings Metadichol helped to lower his fasting blood sugar level from 300 mg/dl to normal in 6 weeks. His HBA1C was reduced from 9.8% to 6.2% in 12 weeks. After 32 more months, his diabetic indicators remain normal. Interpretation Metadichol is safe and effective in controlling blood sugar and HbA1C levels in humans. Metadichol has been shown to bind to the vitamin D receptor (2) as an inverse agonist. However, it acts more like a protean agonist ligand (4) to increase or decrease activity depending on the system. Since Metadichol has no known negative side effects and consists of natural components of common foods, Metadichol has the potential to serve as a novel treatment for type 2 diabetes.
Full-text available
In recent years, vitamin D has been received increased attention due to the resurgence of vitamin D deficiency and rickets in developed countries and the identification of extraskeletal effects of vitamin D, suggesting unexpected benefits of vitamin D in health and disease, beyond bone health. The possibility of extraskeletal effects of vitamin D was first noted with the discovery of the vitamin D receptor (VDR) in tissues and cells that are not involved in maintaining mineral homeostasis and bone health, including skin, placenta, pancreas, breast, prostate and colon cancer cells, and activated T cells. However, the biological significance of the expression of the VDR in different tissues is not fully understood, and the role of vitamin D in extraskeletal health has been a matter of debate. This report summarizes recent research on the roles for vitamin D in cancer, immunity and autoimmune diseases, cardiovascular and respiratory health, pregnancy, obesity, erythropoiesis, diabetes, muscle function, and aging.
Obesity, type 2 diabetes mellitus and cardiovascular disease are at epidemic proportions in developed nations globally, representing major causes of ill-health and premature death. The search for drug targets to counter the growing prevalence of metabolic diseases has uncovered G-protein-coupled receptor 120 (GPR120). GPR120 agonism has been shown to improve inflammation and metabolic health on a systemic level via regulation of adiposity, gastrointestinal peptide secretion, taste preference and glucose homeostasis. Therefore, GPR120 agonists present as a novel therapeutic option that could be exploited for the treatment of impaired metabolic health. This review summarizes the current knowledge of GPR120 functionality and the potential applications of GPR120-specific agonists for the treatment of disease states such as obesity, type 2 diabetes mellitus and cardiovascular disease.
The effects of policosanol (50–500 mg/kg) administered orally for 24 months to Sprague Dawley rats of both sexes were investigated. No differences related to daily clinical observations, weight gain, food consumption, or mortality (survival analysis) between groups were found. Histopathological study showed that the frequency of the occurrence of non-neoplastic and neoplastic (benign and malignant) lesions was similar in the control and policosanol-treated groups. The lesions observed in this study were similar to the spontaneous lesions reported in this species in previous studies. Since no drug-related increase in the occurrence of malignant or benign neoplasms was found, nor acceleration in tumors growth in any specific group was observed, this study shows no evidence of policosanol induced carcinogenicity in this strain of rats. © 1994 Wiley-Liss, Inc.
The superfamily of G protein-coupled receptors (GPCRs) includes at least 800 seven-transmembrane receptors that participate in diverse physiological and pathological functions. GPCRs are the most successful targets of modern medicine, and approximately 36% of marketed pharmaceuticals target human GPCRs. However, the endogenous ligands of more than 140 GPCRs remain unidentified, leaving the natural functions of those GPCRs in doubt. These are the so-called orphan GPCRs, a great source of drug targets. This review focuses on the signaling transduction pathways of the adhesion GPCR family, the LGR subfamily, and the PSGR subfamily, and their potential functions in immunology, development, and cancers. In this review, we present the current approaches and difficulties of orphan GPCR deorphanization and characterization.
Omega-3 fatty acids (omega-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Here, we show that the G protein-coupled receptor 120 (GPR120) functions as an omega-3 FA receptor/sensor. Stimulation of GPR120 with omega-3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high-fat diet with or without omega-3 FA supplementation. The omega-3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. In conclusion, GPR120 is a functional omega-3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation.
Vitamin D, acting through its active metabolite 1,25(OH)(2)D(3), exerts its influence on many physiologic processes in addition to the regulation of calcium and phosphate homeostasis. These processes include the immune system. Both the adaptive and innate immune systems are affected by 1,25(OH)(2)D(3) and its receptor, and the cells involved express not only the vitamin D receptor but also, in most cases, the enzyme CYP27B1, which produces 1,25(OH)(2)D(3). Both the vitamin D receptor and CYP27B1 can be constitutive or induced by the ligands that activate the immune processes in these cells, providing feedback loops that help regulate the immune response. In general, 1,25(OH)(2)D(3) suppresses most elements of the adaptive immune system while inducing most elements of the innate immune system. Thus 1,25(OH)(2)D(3) may be protective against various autoimmune diseases and may limit graft rejection by suppressing adaptive immunity while enhancing the first line of defense against invading microorganisms via upregulation of innate immunity.