. 2020 Sep 2;21(17):6358. doi: 10.3390/ijms21176358

Table 1.

Transgenic mouse models of whole-body and tissue-specific modulation of total and species-specific ceramide and sphingolipid pools.

Mouse Models	Diet/Treatment	BW/BC	Plasma Changes	Tissue Changes	Readouts of Insulin Sensitivity	Readouts of Insulin Signaling	References
Degs1^+/−	CD (7w)	-	-	SkM ↓ Cer/DhCer WAT ↓ Cer/DhCer Liver ↓ Cer/DhCer	↑ Insulin sensitivity index ↑ Insulin tolerance	-	Holland et al., 2007 [74]
Degs1^+/−	CD + Dexamethasone (6w + 1w)	-	-		↑↑ Insulin sensitivity index ↑↑ Insulin tolerance	-	Holland et al., 2007 [74]
Sptlc2^+/−	CD (16w)	↔ BW	↔	SkM ↔ AT ↔ Liver ↑ Cer	↑ Glucose tolerance ↑ Insulin tolerance ↔ Pyruvate tolerance	AT + Liver ↑↑ INSR phosphorylation ↔ Total INSR ↑↑ Akt p-S473	Li et al., 2011 [80]
Sptlc2^+/−	HFD (16w)	↓ BW gain	↓ SM S1P ↓↓ Cer	SkM ↔ AT ↔ Sphingolipids ↓ Adipocyte size Liver ↑ Cer		SkM + AT + Liver ↑↑ INSR phosphorylation ↔ Total INSR ↑↑ Akt p-S473 SkM + AT ↑ GLUT4 translocation
Sms2^+/−	CD (16w)	↔ BW	-	SkM ↓ SM ↑↑ Cer AT ↓ SM Liver ↓ SM ↑↑ Cer	↑ Glucose tolerance ↑ Insulin tolerance SkM + WAT ↑ glucose uptake	Liver ↑↑ Akt p-S473
Sms2^+/−	HFD (16w)	↓ BW gain	-	-	↑ Glucose tolerance ↑ Insulin tolerance ↔ Pyruvate tolerance	-
Cerk^−/−	HFD (11w)	↓ BW gain	-	Brain ↔ C1P AT ↓↓ Adipocyte size ↓↓ Inflammation	↑ Glucose tolerance	eWAT ↑↑ Glut4 + INSR expression	Mitsutake et al., 2012 [87]
CerS2^−/−	CD	↓ BW ↔ BC	-	Liver ↓↓ C22, C24 Cer ↑↑ C16 Cer, HexCer, SM ↑↑ Sphinganine ↑↑ nSMase activity ↓ glycogen storage	↑ Fasting/Fed plasma glucose ↓ Insulin tolerance ↓ Glucose tolerance	Liver ↓↓ p-INSR, Akt p-S473 SkM/AT ↔	Park et al., 2013 [88]
CerS2^+/−	CD (12w)	↔ BW gain ↓ BW/Lean mass	-	Liver ↓↓ C22:0/C24:0 Cer ↑↑ C16:0 GlcCer ↑↑ C16:0 DhSM ↑↑ C16:0 ↓↓ C24:0 DhCer	↔ Plasma Insulin ↔ Glucose tolerance ↔ Insulin tolerance	-	Raichur et al., 2014 [89]
CerS2^+/−	HFD (12w)	↔ BW gain ↑↑ Fat mass/Lean mass	-	Liver ↑ weight ↑ TAG ↑ macrophages ↑↑ C16:0, C18:0, C24:1 Cer ↑ Total Cer ↓↓ Total DhCer ↑ C16:0, C18:1, C24:1 SM ↓↓ C26:0 SM ↑↑ Sphinganine, Sphingosine ↑↑ C16:0 GlcCer ↓↓ C22:0, C24:0 GlcCer	↑ Fed and Fasted plasma Insulin ↓ Glucose tolerance ↓ Insulin tolerance	-	Raichur et al., 2014 [89]
CerS6^−/−	CD (17w)	↓ BW gain	-	-	↑ Glucose tolerance ↔ Insulin tolerance	-	Turpin et al., 2014 [82]
CerS6^−/−	HFD (17w)	↓ BW gain ↓ Fat mass	-	WAT ↓↓ Adipocyte size ↓↓ MAC2 positive cells ↓↓ C16:0 Cer ↑ C18:0 Cer BAT ↓↓ C16:0 Cer ↓↓ LD size ↑↑ Lipolysis, ↑↑ β-oxydation capacity Liver ↓↓ C16:0 Cer SkM ↔ Cer	↓ Serum insulin ↑ Glucose tolerance ↑ Insulin tolerance	Liver ↑↑ Akt p-T308, p-S473 ↑↑ p-GSK3β SkM ↔
Cers6^ΔBAT	HFD (17w)	↔ BW gain ↓ Fat mass	-	BAT ↑↑ β-oxydation capacity	↑ Glucose tolerance ↔ Insulin tolerance	-
Cers6^ΔLiver	HFD (17w)	↓ BW gain	-	Liver ↓↓ C16:0 Cer, DhCer	↑ Glucose tolerance ↔ Insulin tolerance	-
Liver-specific overexpression of AC	HFD + Dox (8w)	↔ BW gain	↓↓ C16:0, C18:0, Total Cer ↓↓ Sphingosine Sphinganine	Liver ↓ weight ↓↓ C16:0, C18:0, C20:0 Cer ↓ Sphingosine ↓↓ TAG ↑↑ DAG ↓ FA synthesis and uptake gene expression AT ↓ GlcCer, DhCer, LacCer ↓↓ Sphingosine Sphinganine Fat pad weight redistribution ↓ inflammation	↑ Glucose tolerance ↑ Insulin tolerance ↑ HE clamp gWAT + sWAT + mWAT ↑↑ Glucose uptake	Liver + gWAT ↑↑ Akt p-S473	Xia et al., 2015 [90]
	CD + Dox (8w)	-	-	-	↑ Glucose tolerance	-
	HFD − HFD + Dox (8w–8w)	-	-	Liver ↑↑ TAG ↓↓ C16:0 C18:0 Cer	↔ Insulin tolerance (3d post-induction)	-
AT-specific overexpression of AC	HFD + Dox (8w)	↔ BW gain	↓ Cer GluCer ↑↑ Sphingosine Sphinganine ↑↑ S1P	mWAT+ gWAT + sWAT ↓ weight (gWAT) ↓↓ C16:0, C18:0, Total Cer ↓ Inflammation Liver ↓↓ TAG ↓↓ C16:0 C18:0 Cer	↑ Glucose tolerance ↑ Insulin tolerance ↑ HE clamp gWAT + sWAT + mWAT ↑↑ Glucose uptake	Liver + gWAT ↑↑ Akt p-S473	Xia et al., 2015 [90]
	CD + Dox (8w)	-	-	mWAT ↓ C18:0, C24:0, C24:1 Total Cer Liver ↓ Total Cer ↓↓ TAG	↑ Glucose tolerance	-
	HFD − HFD + Dox (8w–8w)	-	-	Liver ↓↓ C16:0, C18:0 Cer ↓↓ TAG	↑ Insulin tolerance (3d post-induction)	-
CerS5^−/−	CD (16w)	↔ BW ↔ eWAT mass	↑↑ C24;0 Cer, SM ↓ S1P	SkM ↓ C16:0 Cer Liver ↓↓ C16:0 SM eWAT ↔	↔ Glucose tolerance ↔ Insulin tolerance	eWAT ↑ Akt p-S473	Gosejacob et al., 2016 [91]
CerS5^−/−	HFD (16w)	↓ BW gain ↓ eWAT mass	↓ C16:0, C20:0 SM ↓ S1P	SkM ↓↓ C16:0, C18:0 Cer, SM Liver ↓↓ C16:0 Cer, SM ↑ C18:0 SM eWAT ↓↓ C16:0, C18:0 Cer ↓↓ Adipocyte size ↓ proinflammatory cytokines	↑ Glucose tolerance ↑ Insulin tolerance	-	Gosejacob et al., 2016 [91]
Sms2^−/−	CD (12–23w)	↔ BW	↓ C22:0, 24:0 SM ↑↑ C20:0-C24:0 Cer ↑↑ C22:0 HexCer	Liver ↓↓ C20:0-C24:0 SM ↑↑ C20–24:0 HexCer SkM Very few modifications in SM or Cer content ↔ TAG, DAG	↔ Fasting plasma insulin ↔ Fasting plasma glucose ↔ HOMA-IR ↑ Glucose tolerance ↑ Insulin tolerance ↑ 18F-FDG clearance	Liver/SkM ↑↑ Akt p-S473 mWAT ↓↓ Akt p-S473	Sugimoto et al., 2016 [92]
Sms2^−/−	HFD (12–23w)	↓ BW gain	↓ C16:0-C24:0 SM ↑↑ C20:0-C24:0 Cer ↑↑ C22:0 HexCer	Liver ↓ C18:0-C22:0 SM ↑↑ C22:0 Cer ↓↓ C24:1 DhCer ↑↑ C16:0-C22:0 HexCer SkM ↓ TAG, DAG ↔ NEFA	↓ Fasting plasma insulin ↔ Fasting plasma glucose ↓ HOMA-IR ↑ Glucose tolerance ↑ Insulin tolerance ↑ ¹⁸F-FDG clearance SkM + Liver + Heart ↑ ¹⁸F-FDG uptake	Liver/SkM ↑↑ p-INSR, Akt p-S473 mWAT ↑↑ Akt p-S473
Sms2^ΔLiver	HFD (32w)	↔ BW	↓ C20:0–24:0 SM ↑ C22:0, 24:0, 24:1 Cer ↑ HexCer	Liver ↓ C20:0–24:0 SM ↑↑ HexCer SkM ↔	↔ Fasting plasma glucose ↔ Fasting plasma insulin ↔ Glucose tolerance ↔ Insulin tolerance	-
Sptlc2^ΔAdipo	CD (12–16w)	-	↔ Cer, DhCer, DHC, GM3	Primary Adipocytes eWAT ↓ C22:0, C24:0, C24:1, Total Cer sWAT ↓↓ All Cer BAT ↓↓ C22:0, C24:0, C24:1, Total Cer AT eWAT ↓ Total Cer, ↓↓ Adipocyte size sWAT ↓ C16:0, C24:0, Total Cer ↓↓ DhCer, MHCer, ↓↓ Adipocyte size ↑↑ Thermogenic gene expression, ↑ Uncoupled respiration and OCR BAT ↓↓ C24:0, C24:1, Total Cer	↔ Fed/Fasting plasma glucose ↔ HOMA-IR ↑ Glucose tolerance	-	Chaurasia et al., 2016 [79]
Sptlc2^ΔAdipo	HFD (12–16w)	↓ BW gain ↓ Fat mass/Lean mass ratio	-	BAT ↑ Basal respiration Liver ↓ Lipid storage	↓ Fed/Fasting plasma glucose ↑ HOMA-IR ↑ Glucose tolerance ↑ HE clamp Glucose uptake sWAT ↑ eWAT + BAT ↑↑ SkM ↔	-	Chaurasia et al., 2016 [79]
CerS6 KD (ASO)	HFD (18w + 6w ASO)	↓ BW and Fat mass	-	Liver ↓ TAG ↑↑ Glycogen ↑ Gys2 mRNA	↔ Fed blood glucose ↓ Fed/Fasting plasma Insulin ↓ HOMA-IR ↔ Glucose tolerance ↑ Insulin tolerance	-	Raichur et al., 2019 [83]
CerS6 KD (ASO)	CD (ob/ob)	↓ BW gain ↓ Fat mass (compared to pre-treatment)	↓↓ C16:0 Cer ↑↑ C18:0, C20:0 Cer ↑ C22:0, C24:0, C24:1 Cer	Liver ↓↓ C16:0 Cer ↑↑ C20:0, C22:0, C24:0, C24:1 Cer	↓ Fasted plasma glucose ↓ Fasted plasma insulin ↑ HOMA-IR ↑ Glucose tolerance ↑ Insulin tolerance	-	Raichur et al., 2019 [83]
CerS1^−/−	HFD (17w)	↓ BW gain ↓ Fat mass	-	SkM ↓↓ C18:0 Cer, DhCer, SM ↑↑ C16:0, C22:0, C24:0, C24:1 Cer, DhCer, SM ↔ DAG TAG Heart + Liver + WAT ↔ Cer, DhCer, SM	↑ Glucose tolerance ↑ Insulin tolerance	-	Turpin-Nolan et al., 2019 [85]
CerS1^ΔSkM	HFD (17w)	↔ BW gain ↔ Fat mass	-	SkM ↓↓ C18:0 Cer, DhCer ↑↑ C16:0 Cer ↑↑ C22:1, C24:0, C24:1 Cer, DhCer, SM ↓↓ C22:0 Cer ↔ DAG TAG Heart + Liver + WAT ↔ Cer	↑ Glucose tolerance ↑ Insulin tolerance ↑ HE Clamp (↑ suppression of hepatic glucose production) Glucose uptake SkM ↑ (Trend)	↔ Akt p-T308, p-S473 ↔ PP2A activity
CerS5^ΔSkM + CerS6^ΔSkM	HFD (17w)	↔ BW gain ↔ Fat mass	-	SkM + Heart + Liver+ WAT ↔ Cer, DhCer, SM	↔ Glucose tolerance ↔ Insulin tolerance	-
ob/ob Degs1^{Rosa26/ERT2-Cre}	CD (12w)	↓ BW gain ↓ Fat mass	↓↓ Cer/DhCer, Cer ↓↓ SM, Sphingosine	Liver + WAT + SkM ↓↓ Cer/DhCer ↑↑ DhCer eWAT + sWAT ↓ Adipocyte size ↓ SM ↔ Cer Liver ↓↓ LD area	↑ Glucose tolerance ↑ Insulin tolerance	-	Chaurassia et al., 2019 [81]
Degs1^ΔAdipo	HFD (12w)	↔ BW	↔ Cer/DhCer	eWAT + sWAT+ BAT + SkM ↓↓ Cer/DhCer ↔ Cer Liver ↔ Cer/DhCer, Cer Liver + SkM ↓↓ SM	↓ Fed/Fasting plasma glucose ↓ Serum insulin ↑ Glucose tolerance ↑ Insulin tolerance	-
Degs1^ΔLiver	HFD (12w)	↔ BW	↓↓ Cer/DhCer ↓↓ Cer ↑↑ DhCer ↓↓ SM	Liver + SkM ↓↓ Cer/DhCer SkM ↓↓ SM	↔ Fed/Fasting plasma glucose ↓ Serum insulin ↑ Glucose tolerance ↑ Insulin tolerance	-
Degs1^{ΔLiver/Adipo}	HFD (12w)	↔ BW	↓↓ Cer/DhCer ↓↓ Cer ↑↑ DhCer ↓↓ SM	BAT + Liver + eWAT + sWAT + SkM ↓ Cer/DhCer ↓↓ Cer ↑↑ DhCer Liver + SkM ↓↓ SM	↓ Fed/Fasting plasma glucose ↓ Serum insulin ↑ Glucose tolerance ↑ Insulin tolerance	-
CerS5^−/−	HFD (13–17w)	↔ BW ↔ Fat mass	-	Liver ↓↓ C16:0, C22:0, C24:0 Cer	↔ Glucose tolerance ↓ Insulin tolerance	-	Hammerschmidt et al., 2019 [84]
CerS6^−/−	HFD (13–17w)	↓ BW gain ↓↓ Fat mass	-	Liver ↓↓ C16:0 ↓ C16:1	↑ Glucose tolerance ↑ Insulin tolerance	-
CerS6^iKO	HFD (13–17w)	↓ BW gain	-	Liver ↓↓ C16:0	↑ Glucose tolerance ↑ Insulin tolerance	-
CerS6^fl/fl + AAV8-TBG-iCre	HFD (13–17w)	↔ BW ↔ Fat mass	-	Liver ↓ C16:0	↑ Glucose tolerance ↔ Insulin tolerance ↔ Pyruvate tolerance	-
WT + AAV8-TBG-CerS6	HFD (13–17w)	↔ BW-	-	Liver ↑↑ C16:0	↔ Glucose tolerance ↔ Insulin tolerance ↓ Pyruvate tolerance	-

Table legend: ↑ increase; ↑↑ large increase; ↓ decrease; ↓↓ large decrease; ↔ no change; AC acid ceramidase; Akt protein kinase B; AT adipose tissue; BAT brown AT; BC body composition; BW bodyweight; CD chow diet; Cer Ceramide; d day; DAG diacylglycerol; DhCer dihydroceramide; Dox doxycycline; GLUT4 glucose transporter type 4; GlcCer glucosylceramide; GSK3β glycogen synthase kinase 3β; Gys2 Glycogen synthase 2; HE clamp hyperinsulinemic euglycemic clamp; HexCer hexosylceramide; HFD high-fat diet; HOMA-IR homeostatic model assessment for insulin resistance; INSR insulin receptor; LacCer lactosylceramide; LD lipid droplet; MHCer monohexosylceramide; NEFA non esterified fatty acids; PP2A protein phosphatase 2A; S1P sphingosine-1-phosphate; SkM skeletal muscle; SM sphingomyelin; TAG triacylglycerol; w week; WAT white AT.