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the expression of peroxisome proliferator-activated receptor alpha (Ppara) and a decrease in the expression of acetyl-
CoA carboxylase 2 (Acc2) genes.

Conclusion: Our data suggest that RORγ regulates body weight and lipid metabolism genes and its modulation may be
beneficial for the management of obesity and related lipid metabolic disorders.

Keywords: Lipid metabolism, triglycerides, retinoic acid-related orphan receptor γ, peroxisome proliferator-activated receptors,
sterol response element binding proteins

INTRODUCTION
Obesity is a major risk factor that leads to the development of other metabolic disorders such as
hyperlipidemia and hepatic steatosis. Ectopic accumulation of fat in the liver causes insulin resistance
[1]
by activating various cellular stress and inflammatory signaling pathways . The liver plays an important
role in lipid metabolism that involves several key proteins and transcription factors to maintain lipid
[2]
homeostasis . Various cellular regulators that include several transcription factors control biosynthesis,
[3]
oxidation, uptake, and secretion of lipids in the liver . Peroxisome proliferator-activated receptors
(PPARs), which serve as hepatic lipid sensors, have been demonstrated to play a critical role in lipid
[4,5]
metabolism by controlling the enzymes through various signaling events . Peroxisome proliferator-
activated receptor α (PPARα) is highly expressed in the liver and is primarily involved in the regulation
of enzymes crucial for fatty acid oxidation. It also plays a role in regulating genes that control fatty acid
[6]
elongation, desaturation and transport . On the other hand, peroxisome proliferator-activated receptor
[7]
γ (PPARγ), which is expressed at low levels in the liver , controls the upregulation of a subset of the
[8]
lipogenic genes that are involved in lipid synthesis and accumulation . Besides PPARs, the sterol response
element binding proteins (SREBPs) that act as nutrient sensing transcription factors are also involved in
[9]
the transcriptional control of the lipogenic gene expression . Sterol regulatory-element binding protein 1c
(SREBP-1c) is a transcription factor that primarily upregulates the transcription of genes involved in fatty
acid synthesis. In contrast, sterol regulatory-element binding protein 2 (SREBP-2) controls the activation of
genes responsible mainly for cholesterol synthesis and uptake, as opposed to fatty acid synthesis. However,
sterol regulatory-element binding protein 1a (SREBP-1a) leads to the activation of genes involved in both
pathways [10,11] .

[12]
The transcriptional networks of orphan nuclear receptors govern the hepatic metabolic pathways . The
retinoic acid-related orphan receptor γ (RORγ), a member of the ROR subfamily of nuclear receptors,
[13]
has been implicated in the control of a variety of physiological processes . RORγ binds to specific ROR-
responsive elements at its genomic targets to constitutively activate the gene expression in the absence of a
[14]
ligand . Global RORγ-deficient mice are born healthy and fertile but die within the first four months after
[15]
birth due to high incidence of T-cell lymphomas in the thymus . The physiological functions of RORγ,
[16]
expressed in various peripheral tissues , are still poorly understood. RORγ has been shown to regulate
the circadian expression of glucose and lipid metabolism genes [17,18] . Pharmacological inhibition of RORγ
[19]
has been shown to reduce food intake and body weight gain . However, effect of Rorγ gene deletion on
body weight and hepatic lipids is not well studied. Therefore, in this study, we investigated the effect of Rorγ
gene deletion on body weight and hepatic lipids using a knockout (KO) mouse model. We also studied the
expression of downstream lipid metabolism genes that are regulated directly or indirectly by RORγ.

METHODS
Materials
Infinity cholesterol (catalog # TR13421) and Infinity triglyceride (catalog # TR22421) reagent kits were
TM
purchased from Thermo Scientific (Middletown, VA). TRIzol (catalog #15596018) was purchased from