Table 1.

RBP4 mouse models and human mutations and their phenotypes in different organs systems and processes.

Organ System or Process (in Alphabetical Order)	Mouse Model Phenotypes	Human Mutation Phenotypes
adipose tissue lipolysis	lower circulating levels of non-esterified fatty acids in global RBP4 knockout [36] increased circulating levels of non-esterified fatty acids in adipocyte-specific RBP4 overexpression [44]
behavior and neurological function	decreased locomotor activity, increased anxiety-like behavior, neuronal loss, gliosis in cortex and hippocampus, and reduction in proliferating neuroblasts in subventricular zone in global RBP4 knockout [99]
cardiovascular regulation	lower blood pressure, partial protection from angiotensin 2-induced hypertension, and reduced cardiac hypertrophy in global RBP4 knockout [100] higher blood pressure in muscle-specific RBP4 overexpression [100] protection from cardiac remodeling and cardiac dysfunction after acute myocardial infarction by cardiac-specific RBP4 knockdown [101]
cold tolerance	lower core body temperature, reduced thermogenic activation, and diminished hormone-sensitive lipase activation in subcutaneous white adipose tissue upon cold exposure in global RBP4 knockout [102]
embryonic development	viable embryos with mild and temporary developmental heart abnormalities in global RBP4 knockout [103] vitamin A deficiency before and during pregnancy leads to severe embryonic malformations (smaller size, undetectable or abnormal midfacial regions and forelimbs, and exencephaly) in global RBP4 knockout [73]	developmental abnormalities in homozygous c.11 + 1G > A mutation [104]
insulin sensitivity and glucose tolerance	increased insulin sensitivity in global RBP4 knockout [36] insulin resistance at 12 weeks of age in muscle-specific overexpression of RBP4 [36] no effect on insulin sensitivity and glucose tolerance (normal chow and high-fat diet) in global RBP4 knockout [105] glucose tolerance not impaired in acute liver-specific RBP4 overexpression [40] no effect of muscle-specific RBP4 overexpression on serum insulin levels and insulin sensitivity [106] improved insulin responses and lower adipose tissue inflammation and CD4+ T-cell activation in global RBP4 knockout (on normal chow and high-fat diet; analyzed after feeding low vitamin A diet for 4–5 generations prior to characterization) [107] impaired glucose tolerance and insulin sensitivity and increased adipose tissue inflammation in muscle-specific RBP4 overexpression [107,108] glucose intolerance in adipocyte-specific RBP4 overexpression [44] no alterations in insulin sensitivity or glucose tolerance on control or high-fat/high-sucrose diet in hepatocyte-specific RBP4 knockout [35] insulin response and glucose tolerance not impaired (on normal chow and high-fat diet) in long term liver-specific RBP4 overexpression [39] decreased insulin sensitivity and glucose tolerance through dynamic pancreatic β-cell dysfunction in CAG promoter driven RBP4 transgenic mice [109]
liver fat	hepatic steatosis and increased uptake of non-esterified fatty acids and elevated gluconeogenic gene expression (when fed high-fat diet) in liver by adipocyte-specific overexpression of human RBP4 [44]
retinoid homeostasis	circulating retinol levels decrease by ~90% in global RBP4 knockout [55] increased hepatic retinol and retinyl ester content at the age of 5 months in global RBP4 knockout [55] rescue of RBP4 and retinol serum levels when RBP4 was overexpressed in muscle of RBP4-deficient mice [46] increased utilization of lipoprotein-derived retinyl esters in global RBP4 knockout [52] increased serum RBP4 and retinol levels, decreased hepatic retinyl ester levels, and increased RAR activation in the stromal-vascular fraction of epididymal white adipose tissue by acute liver-specific RBP4 overexpression [40] serum retinol levels below detection threshold in global RBP4 knockout [110] increased RBP4 levels in adipose tissue and unaltered circulating RBP4 and retinol levels on normal chow, while increased on high-fat diet in adipocyte-specific RBP4 overexpression [44] serum RBP4 undetectable, circulating retinol levels reduced by more than 93%, and hepatic retinol and retinyl ester content unchanged in hepatocyte-specific RBP4 knockout [35] rescue of plasma RBP4 and retinol levels when human RBP4 open reading frame cloned into mouse Rbp4 locus of RBP4-deficient mice [111] increased serum RBP4 and retinol levels and unaltered hepatic retinyl ester levels in long-term liver-specific RBP4 overexpression [39]	undetectable serum RBP4 and reduced serum retinol levels in compound heterozygous p.I59N and p.G93D mutation [112] undetectable serum RBP4 levels and reduced serum retinol concentrations in homozygous c.11 + 1G > A mutation [104] poor binding of mutated RBP4 to retinol but higher affinity to STRA6 in heterozygous p.A73T and p.A75T mutation [113] undetectable serum RBP4 levels in bi-allelic c.248 + 1G > A mutation [114]
vision	impaired retinal function and visual acuity after birth which is normalized at the age of 4–5 months when diet is vitamin A sufficient and which cannot be normalized on vitamin A-depleted diet in global RBP4 knockout [55] progressive retinal degeneration in muscle-specific RBP4 overexpression [106] suppression of visual defects when RBP4 was overexpressed in muscle of RBP4-deficient mice [46] severe and persistent visual defects in global RBP4 knockout [110] rescue of retinal function when human RBP4 open reading frame placed into mouse Rbp4 locus of RBP4-deficient mice [111]	night blindness and modest retinal dystrophy in compound heterozygous p.I59N and p.G93D mutation [112,115] retinal dystrophy in homozygous c.11 + 1G > A mutation [104] autosomal dominant congenital eye malformations (incl. microphthalmia, anophthalmia, and coloboma disease) in heterozygous p.A73T and p.A75T mutation [113] retinal dystrophy and ocular coloboma in bi-allelic c.248 + 1G > A mutation [114] retinitis pigmentosa in homozygous c.67 C > T mutation [116]