MyMedR

Displaying all 8 publications

Abstract:

Sort:

Fulltext Conjugating uncoupler compounds with hydrophobic hydrocarbon chains to achieve adipose tissue selective drug accumulation

Ng MY, Song ZJ, Venkatesan G, Rodriguez-Cuenca S, West JA, Yang S, et al.

Sci Rep, 2024 Feb 28;14(1):4932.
PMID: 38418847 DOI: 10.1038/s41598-024-54466-2

One potential approach for treating obesity is to increase energy expenditure in brown and white adipose tissue. Here we aimed to achieve this outcome by targeting mitochondrial uncoupler compounds selectively to adipose tissue, thus avoiding side effects from uncoupling in other tissues. Selective drug accumulation in adipose tissue has been observed with many lipophilic compounds and dyes. Hence, we explored the feasibility of conjugating uncoupler compounds with a lipophilic C8-hydrocarbon chain via an ether bond. We found that substituting the trifluoromethoxy group in the uncoupler FCCP with a C8-hydrocarbon chain resulted in potent uncoupling activity. Nonetheless, the compound did not elicit therapeutic effects in mice, likely as a consequence of metabolic instability resulting from rapid ether bond cleavage. A lipophilic analog of the uncoupler compound 2,6-dinitrophenol, in which a C8-hydrocarbon chain was conjugated via an ether bond in the para-position (2,6-dinitro-4-(octyloxy)phenol), exhibited increased uncoupling activity compared to the parent compound. However, in vivo pharmacokinetics studies suggested that 2,6-dinitro-4-(octyloxy)phenol was also metabolically unstable. In conclusion, conjugation of a hydrophobic hydrocarbon chain to uncoupler compounds resulted in sustained or improved uncoupling activity. However, an ether bond linkage led to metabolic instability, indicating the need to conjugate lipophilic groups via other chemical bonds.

Matched MeSH terms: Adipose Tissue, White/metabolism
Fulltext Molecular Mechanisms of Adipogenesis: The Anti-adipogenic Role of AMP-Activated Protein Kinase

Ahmad B, Serpell CJ, Fong IL, Wong EH

Front Mol Biosci, 2020;7:76.
PMID: 32457917 DOI: 10.3389/fmolb.2020.00076

Obesity is now a widespread disorder, and its prevalence has become a critical concern worldwide, due to its association with common co-morbidities like cancer, cardiovascular diseases and diabetes. Adipose tissue is an endocrine organ and therefore plays a critical role in the survival of an individual, but its dysfunction or excess is directly linked to obesity. The journey from multipotent mesenchymal stem cells to the formation of mature adipocytes is a well-orchestrated program which requires the expression of several genes, their transcriptional factors, and signaling intermediates from numerous pathways. Understanding all the intricacies of adipogenesis is vital if we are to counter the current epidemic of obesity because the limited understanding of these intricacies is the main barrier to the development of potent therapeutic strategies against obesity. In particular, AMP-Activated Protein Kinase (AMPK) plays a crucial role in regulating adipogenesis - it is arguably the central cellular energy regulation protein of the body. Since AMPK promotes the development of brown adipose tissue over that of white adipose tissue, special attention has been given to its role in adipose tissue development in recent years. In this review, we describe the molecular mechanisms involved in adipogenesis, the role of signaling pathways and the substantial role of activated AMPK in the inhibition of adiposity, concluding with observations which will support the development of novel chemotherapies against obesity epidemics.

Matched MeSH terms: Adipose Tissue, White
Fulltext Lipoprotein lipase expression, serum lipid and tissue lipid deposition in orally-administered glycyrrhizic acid-treated rats

Lim WY, Chia YY, Liong SY, Ton SH, Kadir KA, Husain SN

Lipids Health Dis, 2009;8:31.
PMID: 19638239 DOI: 10.1186/1476-511X-8-31

The metabolic syndrome (MetS) is a cluster of metabolic abnormalities comprising visceral obesity, dyslipidaemia and insulin resistance (IR). With the onset of IR, the expression of lipoprotein lipase (LPL), a key regulator of lipoprotein metabolism, is reduced. Increased activation of glucocorticoid receptors results in MetS symptoms and is thus speculated to have a role in the pathophysiology of the MetS. Glycyrrhizic acid (GA), the bioactive constituent of licorice roots (Glycyrrhiza glabra) inhibits 11beta-hydroxysteroid dehydrogenase type 1 that catalyzes the activation of glucocorticoids. Thus, oral administration of GA is postulated to ameliorate the MetS.

Matched MeSH terms: Adipose Tissue, White/cytology; Adipose Tissue, White/drug effects; Adipose Tissue, White/enzymology; Adipose Tissue, White/pathology
Khat (Catha edulis) upregulates lipolytic genes in white adipose tissue of male obese mice (C57BL/6J)

Alshagga MA, Mohamed Z, Seyedan A, Ebling FJP, Alshawsh MA

J Ethnopharmacol, 2020 Nov 15;262:113187.
PMID: 32730892 DOI: 10.1016/j.jep.2020.113187

ETHNOPHARMACOLOGICAL RELEVANCE: Khat (Catha edulis (Vahl) Forssk.) is a herb from the Celastraceae family (also known as qat, gaad, or mirra) that is widely-consumed in East Africa and in the Arabian peninsula. The green leaves and small stems are consumed primarily at recreational and social gatherings, and medicinally for their antidiabetic and appetite-suppression effects.
AIMS: The objectives of this study were to determine the effects of khat and its active alkaloid, cathinone, on food intake and body weight in mice maintained on a high-fat diet, and to investigate its mechanism of action in white adipose tissue and in the hypothalamus.
MATERIALS & METHOD: Adult male mice (C57BL/6J) were fed a high fat diet (HFD) for 8 weeks (n = 30), then divided into 5 groups and treated daily for a further 8 weeks with HFD + vehicle [control (HFD)], HFD + 15 mg/kg orlistat (HFDO), HFD + 200 mg/kg khat extract (HFDK200), HFD + 400 mg/kg khat extract (HFDK400) and HFD + 3.2 mg/kg cathinone (HFDCAT). Treatments were carried out once daily by gastric gavage. Blood and tissue samples were collected for biochemical, hormonal and gene expression analyses.
RESULTS: Khat extracts and orlistat treatment significantly reduced weight gain as compared to control mice on HFD, and cathinone administration completely prevented weight gain in mice fed on HFD. Khat treatment caused a marked reduction in body fat and in serum triglycerides. A dose-dependent effect of khat was observed in reducing serum leptin concentrations. Analysis of gene expression in adipose tissue revealed a significant upregulation of two lipolysis pathway genes:(adipose triglyceride lipase (PNPLA-2) and hormone-sensitive lipase (LIPE). In the hypothalamic there was a significant (P white adipose tissue.

Matched MeSH terms: Adipose Tissue, White/drug effects*; Adipose Tissue, White/metabolism
Transcriptomics expression analysis to unveil the molecular mechanisms underlying the cocoa polyphenol treatment in diet-induced obesity rats

Ali F, Ismail A, Esa NM, Pei CP

Genomics, 2015 Jan;105(1):23-30.
PMID: 25451742 DOI: 10.1016/j.ygeno.2014.11.002

Cocoa polyphenol (CP), due to their biological actions, may be supplementary treatments for adipose tissue-fat gain. However, the molecular mechanism of CPs is still ambiguous. This study investigated the hypothesis that CP treatment modulates expressing of lipid metabolism genes in mesenteric white adipose tissue (MES-WAT). Sprague-Dawley (SD) rats were fed a low-fat (LF) or high-fat (HF) diet for 12 weeks. Thereafter, HFD rats (n = 10/group) were treated at a dose of 600 mg/kg bw/day CPs (HFD + CPs) for 4 weeks. DNA microarray analysis resulted in 753 genes of the 13,008 genes expressed. Bioinformatics tools showed CP treatment significantly decreased gene expression levels for lipogenic enzymes, while increased the mRNA levels responsible for lipolysis enzymes. CP administration differentially regulates gene expression involved in lipid metabolism in MES-WAT. These data unveil a new insight into the molecular mechanisms underlying the pharmacological effect of CPs on obesity biomarkers in obese rats.

Matched MeSH terms: Adipose Tissue, White/metabolism
Fulltext Effects of maternal diet and exercise during pregnancy on glucose metabolism in skeletal muscle and fat of weanling rats

Raipuria M, Bahari H, Morris MJ

PLoS One, 2015;10(4):e0120980.
PMID: 25853572 DOI: 10.1371/journal.pone.0120980

Obesity during pregnancy contributes to the development of metabolic disorders in offspring. Maternal exercise may limit gestational weight gain and ameliorate these programming effects. We previously showed benefits of post-weaning voluntary exercise in offspring from obese dams. Here we examined whether voluntary exercise during pregnancy influences lipid and glucose homeostasis in muscle and fat in offspring of both lean and obese dams. Female Sprague-Dawley rats were fed chow (C) or high fat (F) diet for 6 weeks before mating. Half underwent voluntary exercise (CE/FE) with a running wheel introduced 10 days prior to mating and available until the dams delivered; others remained sedentary (CS/FS). Male and female pups were killed at postnatal day (PND)19 and retroperitoneal fat and gastrocnemius muscle were collected for gene expression. Lean and obese dams achieved similar modest levels of exercise. At PND1, both male and female pups from exercised lean dams were significantly lighter (CE versus CS), with no effect in those from obese dams. At PND19, maternal obesity significantly increased offspring body weight and adiposity, with no effect of maternal exercise. Exercise significantly reduced insulin concentrations in males (CE/FE versus CS/FS), with reduced glucose in male FE pups. In males, maternal obesity significantly decreased muscle myogenic differentiation 1 (MYOD1) and glucose transporter type 4 (GLUT4) mRNA expressions (FS vs CS); these were normalized by exercise. Maternal exercise upregulated adipose GLUT4, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1α) mRNA expression in offspring of dams consuming chow. Modest voluntary exercise during pregnancy was associated with lower birth weight in pups from lean dams. Maternal exercise appeared to decrease the metabolic risk induced by maternal obesity, improving insulin/glucose metabolism, with greater effects in male than female offspring.

Matched MeSH terms: Adipose Tissue, White/metabolism
Fulltext Leptin: a pleitropic factor in physiology

Fayez A Almabhouh, Faizatul Isyraqiah Ahmad Muhammad, Hisham Ibrahim, Harbindarjeet Singh

Journal of Clinical and Health Sciences, 2019;4(2):31-57.
MyJurnal

Leptin, a 16 kDa protein and a product of the ob/ob gene, has a tertiary structure similar to that
of a cytokine. It is primarily secreted by white adipose tissue and its levels in the blood correlate
positively with percentage body fat. Leptin was first identified in 1994 as a major factor that
regulated food intake and energy balance. Leptin in the circulation exists either as a free
monomeric hormone or bound to its soluble receptor. Its serum levels usually range from 0.5 to
37.7 ng/ml in males and 2.0 to 45.2 ng/ml in females. The half-life of leptin is between 20 - 30
minutes and it is eliminated mainly by the kidneys. However, research over the last 25 years
has revealed numerous other physiological roles for leptin, including roles in inflammation,
immune function, neuro-endocrine function, bone metabolism, blood pressure regulation and
sexual maturation. Most of these roles have been identified from studies on leptin deficient
rodents. Apart from energy balance and sexual maturation, where its role is direct and obvious,
its actions on the rest of the other systems are permissive. Actions of leptin are both centrally
and peripherally mediated involving receptors that are widely distributed in the body. Six leptin
receptor isoforms, belonging to the class 1 cytokine receptor family, have been identified.
These receptors are products of the OBR gene. The cellular actions of leptin are mediated
through any one of five different signalling pathways that include the JAK-STAT, PI3K, MAPK,
AMPK, and the mTOR signalling pathways.

Matched MeSH terms: Adipose Tissue, White
Fulltext The physiology of leptin: revisited

Singh, Harbindar Jeet

Medical Health Reviews, 2009;2009(1):95-133.
MyJurnal

Leptin, a 167 amino-acid product of the ob or LEP gene, was first reported in 1994 after a 40-year search that began following the emergence of a mutant strain of mice with hyperphagia, early on-set obesity, and delayed sexual maturation. Since then, leptin deficiency has also been reported in the rat, and more recently in humans. It is secreted constitutively primarily by the white adipose tissue, and in smaller quantities by a number of non-adipose tissues. It acts by binding to specific membrane bound leptin receptors, belonging to the class 1 cytokine receptor family, and activating the JAK-STAT system. Leptin regulates appetite and body weight mainly through its actions on the hypothalamus involving the NPYmelanocortin pathway, and, to a lesser extent, through increased energy expenditure by way of sympathoactivation and increased substrate cycling. Its effects on reproduction, puberty in particular, are mediated through actions on the hypothalamic-pituitary-gonadal axis and on the gonads. Leptin also appears to have permissive roles in CNS development during the neonatal period, bone growth and development, and in haemopoietic and immune functions. Although it was its deficiency state that first led to its discovery, it now appears that the clinical significance of leptin lies not only in the consequences of its deficiency but also when it is in excess as occurs in obesity. Emerging evidence is implicating leptin as a link between obesity associated cardiovascular disease risks and infertility. Besides this, leptin is also being implicated as a growth factor in cancer. The story that started with a search for a body weight regulating factor is now unfolding into one that is revealing roles for leptin that stretch beyond the regulation of appetite and body weight.

Matched MeSH terms: Adipose Tissue, White