Pathogenic analysis of post-transplantation obesity: A comprehensive systematic review

Table 1 Screening results

Total	Theme-independent	Non-postoperative obesity	Mechanism-free
298	283	6	2
290	109	90	61
290	270	9	11
290	22	176	12
289	247	7	6
1457	931	288	92

Table 2 Classification results

Total	Liver	Kidney	Heart	Lung
7	/	3	4	/
30	1	7	19	3
0	/	/	/	/
80	6	32	24	13
29	/	13	13	2
146	7	55	60	18

Table 3 Summary of metabolic effects and mechanisms of common

Immunosuppressant	Major metabolic effects	Proposed mechanisms	Ref.
Glucocorticoids	Hyperphagia, central adiposity, insulin resistance	↑ Appetite via central regulation; ↓ adiponectin, ↑ leptin resistance	[11]
Tacrolimus (CNI)	Impaired glucose tolerance, β-cell apoptosis	Inhibition of PI3K/Akt/mTOR; microbiome alterations	[15]
Cyclosporine (CNI)	Dyslipidemia, insulin resistance	Mitochondrial dysfunction, oxidative stress	[18]
Mycophenolate Mofetil	Dyslipidemia	Synergistic effects when combined with steroids/CNIs	[18]
Azathioprine	Less studied; associated with lipid alterations	Likely indirect or combined effects	[18]

CNI: Calcineurin inhibitor.

Table 4 Comparison of post-transplant obesity incidence and influencing factors by organ type

Index	Adult	Child	Activity	Diet	Ref.
Heart transplant	25-40 per cent of patients’ obesity post-transplantation	The lowest incidence of obesity post-transplantation, the lowest risk of obesity relative to other organ groups	Limited heart function and restricted exercise tolerance	The aggressive use of supplemental nutrition via feeding tubes	[23,24]
Kidney transplantation	21% of patients with CKD have obesity, and CKD patients are the main population for kidney transplantation	The highest incidence of obesity, a cumulative incidence 5-year post-transplantation of 27%	Reduced activity due to dialysis	Supplementary caloric intake via peritoneal dialysis	[22,23]
Liver transplantation	23% of liver transplant candidates have class I obesity, 10% have class II, and 4% have class III	The probability of obesity is lower than that of kidney transplantation and higher than that of heart transplantation	have a critical clinical status at time of transplantation in order to reduce activites	have a critical clinical status at time of transplantation in order to reduce food intake	[23,24]

CKD: Chronic kidney disease.

Table 5 Key adipokine alterations in post-transplantation obesity

Adipokine	Change	Mechanism	Metabolic Consequence	Ref.
Leptin	↑ Secretion	PPARγ inhibition→Leptin resistance	↑Appetite,↑ hepatic glucose output	[25,26]
Adiponectin	↓Secretion (30%–50%)	Impaired PPARγ/AMPK axis	↓Fatty acid oxidation→lipid accumulation	[25,27]
Resistin	↑ Secretion	NF-κB activation by oxidative stress	IRS1 inhibition →↓glucose uptake	[25,29]

Table 6 Molecular pathways and key factors in transplant-associated adipogenesis

Mechanism type	Specific ways	Key molecules/factors	Effect
Inflammatory cascade activates adipogenic pathways	Activation of signaling pathways[40,41]	NF-Kb, JAK/STAT, TNF-α, SIRT1, PPARy, C/EBPα	Inflammatory signaling activates NF-κB, JAK/STAT pathways, TNF-α enhances PPARV activity by inhibiting SIRT1 or promoting its phosphorylation and up-regulation of key adipogenic transcription factors drives preadipocyte differentiation
	Epigenetic regulation[36,42]	IL-6, DNMT, Pref-1	Activation of DNMT by IL-6 and inhibition of Pref-1 release the suppression of adipogenesis and alteration of adipogenesis-related gene expression by epigenetic mechanisms
	Extracellular matrix effects[34,35]	Integrin signaling pathway ECM components	Inflammation leads to extracellular matrix sclerosis, which promotes proliferation and differentiation of adipocyte precursors through activation of mechanotransduction by the integrin signaling pathway; aberrant deposition of ECM components regulates adipocyte-matrix interactions and affects adipogenic efficiency
Oxidative stress activates adipogenic pathways	Transcription factor activation[33,38]	ROS, Nrf2, SREBP-1c	ROS activate redox-sensitive transcription factors such as Nrf2, which binds to the SREBP.1c promoter under chronic oxidative stress to directly promote adipogenic gene transcription
	lipid peroxidation[33,38]	4-Hydroxynonenal, ACC, FAS	Oxidative stress leads to lipid peroxidation to generate aldehyde products, and modification of sulfhydryl groups of key adipogenic proteins, such as ACC. FAS, alters their enzymatic activity or stability and promotes lipid synthesis
	Metabolic reprogramming[32,37]	mitochondrial membrane potential, ATP, Acetyl Coenzyme A, AMPK/mTOR pathway	Oxidative stress induces the loss of mitochondrial membrane potential, ATP synthesis decreases cellular energy metabolism from oxidative phosphorylation to glycolysis, increases the generation of acetyl-coenzyme A, which provides substrates for fat synthesis, and at the same time activates the AMPK/mTOR pathway to promote the proliferation and differentiation of adipocyte precursors
Inflammation and oxidative stress synergize	Signal network synergy[33,39]	ROS, IKK complex, NF-κB, TNF-α, NLRP3inflammatory, vesicle	ROS activate IKK complex, promote NFKB nuclear translocation, and up-regulate inflammatory cytokines and adipogenic gene expression: TNF-α induces mitochondrial ROS production, and ROS activate NLRP3 inflammatory vesicles, forming a positive feedback loop and continuously activating the adipogenic pathway

TNF-α: Tumor necrosis factor-alpha; SIRT1: Sirtuin 1; C/EBPα: CCAAT/enhancer-binding protein alpha; IL-6: Interleukin-6; DNMT: DNA methyltransferase; Pref-1: Preadipocyte factor-1; ECM: Extracellular matrix; ROS: Reactive oxygen species; Nrf2: Nuclear factor erythroid 2–related factor 2; SREBP-1c: Sterol regulatory element-binding protein 1c; ACC: Acetyl-CoA carboxylase; FAS: Fatty acid synthase; AMPK: AMP-activated protein kinase; mTOR: Mechanistic target of rapamycin; IKK: IκB kinase; NLRP3: NLR family pyrin domain containing 3.