HIV-1 Viral Protein R Couples Metabolic inflexibility with White Adipose Tissue Thermogenesis

Persons living with HIV (PLWH) manifest chronic disorders of brown and white adipose tissues that lead to diabetes and metabolic syndrome. The mechanisms that link viral factors to defective adipose tissue function and abnormal energy balance in PLWH remain incompletely understood. Here, we explored how the HIV accessory protein viral protein R (Vpr) contributes to adaptive thermogenesis in two mouse models and human adipose tissues. Uncoupling protein 1 (UCP1) gene expression was strongly increased in subcutaneous white adipose tissue (WAT) biopsies from PLWH and in subcutaneous WAT of the Vpr mice, with near-equivalent mRNA copy number. Histology and functional studies confirmed beige transformation in subcutaneous but not visceral WAT in the Vpr mice. Measurements of energy balance indicated Vpr mice displayed metabolic inflexibility and could not shift efficiently from carbohydrate to fat metabolism during day-night cycles. Furthermore, Vpr mice showed a marked inability to defend body temperature when exposed to 4<sup>o</sup>C. Importantly, Vpr couples higher tissue catecholamine levels with UCP1 expression independent of β-adrenergic receptors. Our data reveal surprising deficits of adaptive thermogenesis that drive metabolic inefficiency in HIV-1 Vpr mouse models, providing an expanded role for viral factors in the pathogenesis of metabolic disorders in PLWH.

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HIV-1 Viral Protein R couples metabolic inflexibility with white adipose tissue thermogenesis

Diabetes ◽

10.2337/db20-0888 ◽

2021 ◽

pp. db200888

Author(s):

Neeti Agarwal ◽

Dinakar Iyer ◽

Pradip Saha ◽

Aaron R. Cox ◽

Yan Xia ◽

...

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Viral Protein ◽

Viral Protein R ◽

Metabolic Inflexibility ◽

Hiv 1

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1712-P: HIV-1 Vpr Couples Metabolic Inflexibility with White Adipose Tissue Thermogenesis

Diabetes ◽

10.2337/db20-1712-p ◽

2020 ◽

Vol 69 (Supplement 1) ◽

pp. 1712-P

Author(s):

NEETI AGARWAL ◽

PRADIP SAHA ◽

SEAN M. HARTIG ◽

ASHOK BALASUBRAMANYAM

Keyword(s):

Adipose Tissue ◽

White Adipose Tissue ◽

Metabolic Inflexibility ◽

Hiv 1

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Reduced Expression of Urokinase Plasminogen Activator in Brown Adipose Tissue of Obese Mouse Models

International Journal of Molecular Sciences ◽

10.3390/ijms22073407 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3407

Author(s):

Chung-Ze Wu ◽

Li-Chien Chang ◽

Chao-Wen Cheng ◽

Te-Chao Fang ◽

Yuh-Feng Lin ◽

...

Keyword(s):

Adipose Tissue ◽

Glomerular Filtration Rate ◽

Brown Adipose Tissue ◽

Glomerular Filtration ◽

Plasminogen Activator ◽

Mouse Models ◽

Filtration Rate ◽

Obese Mouse ◽

Adipose Tissues ◽

Brown Adipose

In recent decades, the obesity epidemic has resulted in morbidity and mortality rates increasing globally. In this study, using obese mouse models, we investigated the relationship among urokinase plasminogen activator (uPA), metabolic disorders, glomerular filtration rate, and adipose tissues. Two groups, each comprised of C57BL/6J and BALB/c male mice, were fed a chow diet (CD) and a high fat diet (HFD), respectively. Within the two HFD groups, half of each group were euthanized at 8 weeks (W8) or 16 weeks (W16). Blood, urine and adipose tissues were collected and harvested for evaluation of the effects of obesity. In both mouse models, triglyceride with insulin resistance and body weight increased with duration when fed a HFD in comparison to those in the groups on a CD. In both C57BL/6J and BALB/c HFD mice, levels of serum uPA initially increased significantly in the W8 group, and then the increment decreased in the W16 group. The glomerular filtration rate declined in both HFD groups. The expression of uPA significantly decreased in brown adipose tissue (BAT), but not in white adipose tissue, when compared with that in the CD group. The results suggest a decline in the expression of uPA in BAT in obese m models as the serum uPA increases. There is possibly an association with BAT fibrosis and dysfunction, which may need further study.

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Modulation of NKG2D-Mediated Cytotoxic Functions of Natural Killer Cells by Viral Protein R from HIV-1 Primary Isolates

Journal of Virology ◽

10.1128/jvi.06921-11 ◽

2012 ◽

Vol 86 (3) ◽

pp. 1902-1902

Author(s):

T. N. Q. Pham ◽

J. Richard ◽

F. C. A. Gerard ◽

C. Power ◽

E. A. Cohen

Keyword(s):

Natural Killer Cells ◽

Natural Killer ◽

Viral Protein ◽

Killer Cells ◽

Viral Protein R ◽

Hiv 1

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Tryptophan metabolism activation by indoleamine 2,3-dioxygenase in adipose tissue of obese women: an attempt to maintain immune homeostasis and vascular tone

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00373.2011 ◽

2012 ◽

Vol 303 (2) ◽

pp. R135-R143 ◽

Cited By ~ 47

Author(s):

Isabelle Wolowczuk ◽

Benjamin Hennart ◽

Audrey Leloire ◽

Alban Bessede ◽

Marion Soichot ◽

...

Keyword(s):

Adipose Tissue ◽

T Cell ◽

White Adipose Tissue ◽

Vascular Tone ◽

T Cell Subsets ◽

Low Grade ◽

Adipose Tissues ◽

Indoleamine 2,3 Dioxygenase ◽

Arterial Blood ◽

Ido1 Expression

Human obesity is characterized by chronic low-grade inflammation in white adipose tissue and is often associated with hypertension. The potential induction of indoleamine 2,3-dioxygenase-1 (IDO1), the rate-limiting enzyme in tryptophan/kynurenine degradation pathway, by proinflammatory cytokines, could be associated with these disorders but has remained unexplored in obesity. Using immunohistochemistry, we detected IDO1 expression in white adipose tissue of obese patients, and we focused on its contribution in the regulation of vascular tone and on its immunoregulatory effects. Concentrations of tryptophan and kynurenine were measured in sera of 36 obese and 15 lean women. The expression of IDO1 in corresponding omental and subcutaneous adipose tissues and liver was evaluated. Proinflammatory markers and T-cell subsets were analyzed in adipose tissue via the expression of CD14, IL-18, CD68, TNFα, CD3ε, FOXP3 [a regulatory T-cell (Treg) marker] and RORC (a Th17 marker). In obese subjects, the ratio of kynurenine to tryptophan, which reflects IDO1 activation, is higher than in lean subjects. Furthermore, IDO1 expression in both adipose tissues and liver is increased and is inversely correlated with arterial blood pressure. Inflammation is associated with a T-cell infiltration in obese adipose tissue, with predominance of Th17 in the omental compartment and of Treg in the subcutaneous depot. The Th17/Treg balance is decreased in subcutaneous fat and correlates with IDO1 activation. In contrast, in the omental compartment, despite IDO1 activation, the Th17/Treg balance control is impaired. Taken together, our results suggest that IDO1 activation represents a local compensatory mechanism to limit obesity-induced inflammation and hypertension.

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Beige Fat, Adaptive Thermogenesis, and Its Regulation by Exercise and Thyroid Hormone

Biology ◽

10.3390/biology8030057 ◽

2019 ◽

Vol 8 (3) ◽

pp. 57 ◽

Cited By ~ 6

Author(s):

Kevin J. Phillips

Keyword(s):

Adipose Tissue ◽

Thyroid Hormone ◽

Metabolic Effects ◽

Adipose Tissues ◽

Beige Adipocyte ◽

Adaptive Thermogenesis ◽

Beige Adipocytes ◽

Beige Fat ◽

Beige Cells ◽

Adipocyte Development

While it is now understood that the proper expansion of adipose tissue is critically important for metabolic homeostasis, it is also appreciated that adipose tissues perform far more functions than simply maintaining energy balance. Adipose tissue performs endocrine functions, secreting hormones or adipokines that affect the regulation of extra-adipose tissues, and, under certain conditions, can also be major contributors to energy expenditure and the systemic metabolic rate via the activation of thermogenesis. Adipose thermogenesis takes place in brown and beige adipocytes. While brown adipocytes have been relatively well studied, the study of beige adipocytes has only recently become an area of considerable exploration. Numerous suggestions have been made that beige adipocytes can elicit beneficial metabolic effects on body weight, insulin sensitivity, and lipid levels. However, the potential impact of beige adipocyte thermogenesis on systemic metabolism is not yet clear and an understanding of beige adipocyte development and regulation is also limited. This review will highlight our current understanding of beige adipocytes and select factors that have been reported to elicit the development and activation of thermogenesis in beige cells, with a focus on factors that may represent a link between exercise and ‘beiging’, as well as the role that thyroid hormone signaling plays in beige adipocyte regulation.

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Anti-Obesity Effects of Grateloupia elliptica, a Red Seaweed, in Mice with High-Fat Diet-Induced Obesity via Suppression of Adipogenic Factors in White Adipose Tissue and Increased Thermogenic Factors in Brown Adipose Tissue

Nutrients ◽

10.3390/nu12020308 ◽

2020 ◽

Vol 12 (2) ◽

pp. 308 ◽

Cited By ~ 4

Author(s):

Hyo-Geun Lee ◽

Yu An Lu ◽

Xining Li ◽

Ji-Min Hyun ◽

Hyun-Soo Kim ◽

...

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

White Adipose Tissue ◽

High Fat Diet ◽

Red Seaweed ◽

High Fat ◽

Adipose Tissues ◽

Ppar Γ ◽

Brown Adipose ◽

Treatment Of Obesity

Obesity is a serious metabolic syndrome characterized by high levels of cholesterol, lipids in the blood, and intracellular fat accumulation in adipose tissues. It is known that the suppression of adipogenic protein expression is an effective approach for the treatment of obesity, and regulates fatty acid storage and transportation in adipose tissues. The 60% ethanol extract of Grateloupia elliptica (GEE), a red seaweed from Jeju Island in Korea, was shown to exert anti-adipogenic activity in 3T3-L1 cells and in mice with high-fat diet (HFD)-induced obesity. GEE inhibited intracellular lipid accumulation in 3T3-L1 cells, and significantly reduced expression of adipogenic proteins. In vivo experiments indicated a significant reduction in body weight, as well as white adipose tissue (WAT) weight, including fatty liver, serum triglycerides, total cholesterol, and leptin contents. The expression of the adipogenic proteins, SREBP-1 and PPAR-γ, was significantly decreased by GEE, and the expression of the metabolic regulator protein was increased in WAT. The potential of GEE was shown in WAT, with the downregulation of PPAR-γ and C/EBP-α mRNA; in contrast, in brown adipose tissue (BAT), the thermogenic proteins were increased. Collectively, these research findings suggest the potential of GEE as an effective candidate for the treatment of obesity-related issues via functional foods or pharmaceutical agents.

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HIV-1 Integrase-Targeted Short Peptides Derived from a Viral Protein R Sequence

Molecules ◽

10.3390/molecules23081858 ◽

2018 ◽

Vol 23 (8) ◽

pp. 1858 ◽

Cited By ~ 1

Author(s):

Xue Zhao ◽

Mathieu Métifiot ◽

Evgeny Kiselev ◽

Jacques Kessl ◽

Kasthuraiah Maddali ◽

...

Keyword(s):

Viral Protein ◽

Divalent Metal ◽

Common Mechanism ◽

Strand Transfer ◽

Divalent Metal Ions ◽

Dna Interactions ◽

Inhibitory Potency ◽

New Class ◽

Viral Protein R ◽

Hiv 1

HIV-1 integrase (IN) inhibitors represent a new class of highly effective anti-AIDS therapeutics. Current FDA-approved IN strand transfer inhibitors (INSTIs) share a common mechanism of action that involves chelation of catalytic divalent metal ions. However, the emergence of IN mutants having reduced sensitivity to these inhibitors underlies efforts to derive agents that antagonize IN function by alternate mechanisms. Integrase along with the 96-residue multifunctional accessory protein, viral protein R (Vpr), are both components of the HIV-1 pre-integration complex (PIC). Coordinated interactions within the PIC are important for viral replication. Herein, we report a 7-mer peptide based on the shortened Vpr (69–75) sequence containing a biotin group and a photo-reactive benzoylphenylalanyl residue, and which exhibits low micromolar IN inhibitory potency. Photo-crosslinking experiments have indicated that the peptide directly binds IN. The peptide does not interfere with IN-DNA interactions or induce higher-order, aberrant IN multimerization, suggesting a mode of action for the peptide that is distinct from clinically used INSTIs and developmental allosteric IN inhibitors. This compact Vpr-derived peptide may serve as a valuable pharmacological tool to identify a potential new pharmacologic site.

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