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Gene & Protein in Disease Genetic pleiotropy in birth weight and fat

signaling pathways, primarily through the IGF1 receptor from the differentiation of new adipocytes from pre-
(IGF1R), activate downstream cascades such as PI3K-AKT cursor cells in adipose tissue, primarily regulated by the
and MAPK, which can influence the expression of various nuclear factor PPARγ, along with other proteins such as
transcription factors, including PPAR gamma (PPARγ). CCAAT-enhancer-binding protein, bone morphogenetic
PPARγ plays a crucial role in adipogenesis and lipid protein, and zinc finger protein. The functions of IGF1,
metabolism. Studies have shown that IGF1/2 signaling IGF2, and insulin are mediated through insulin receptors
can upregulate PPARG expression, thereby promoting and IGF receptors, which are closely related and share
adipocyte differentiation and lipid accumulation. This numerous overlapping downstream signaling pathways.
functional link suggests a coordinated mechanism by In pre-adipocytes, IGF1R expression is higher than insulin
which growth factor signaling and metabolic regulation are receptor expression, whereas the opposite pattern is
intertwined and highlights the potential for IGF signaling observed in mature adipocytes. 39,40
to modulate metabolic gene expression through PPARG. 21 Adipogenesis plays a crucial role in numerous
The IGF1 system plays a crucial role as an endocrine physiological and pathophysiological processes including
regulator of fetal growth. 21,22 While IGF2 contributes to obesity. Moreover, the pathogenic mechanisms are not fully
fetal and placental development, evidence from direct understood, and the exact role of adipocyte expansion,
measurements highlights IGF1 as the primary factor remodeling, and activity remains not unequivocal. As
influencing fetal growth. In the fetus, IGF1 and insulin, reported by Spalding et al., individuals with obesity have
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23
rather than growth hormone, serve as the primary drivers more adipocytes added per year than lean individuals,
of growth. 24,25 Insulin promotes the production of IGF1, although the relationship between adipocyte morphology
which facilitates a rapid response to nutritional changes and production appears to be independent of body mass
through the glucose–insulin axis. This mechanism is index. Obesity is associated with impaired white adipose
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crucial during mid-to-late gestation when IGF1 levels tissue expansion and remodeling, which exacerbate ectopic
typically increase to support the accelerated growth that fat deposition and metabolic disturbances. On the other
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occurs in the third trimester. 26,27 Notably, human fetal hand, according to Arner et al., adipocyte lipid storage
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serum IGF1 levels from 15 to 37 weeks of gestational age and removal play a crucial role in maintaining health
are positively correlated with fetal weight. 28-31 Both IGF1 and the development of disease. While high triglyceride
and IGF2 have been widely studied in umbilical cord blood. storage coupled with low removal favors fat accumulation
Cordonal IGF1 levels exhibit a strong positive correlation and obesity, a reduction in both storage and removal
with growth indices, whereas IGF2 demonstrates a impairs lipid buffering capacity, promoting lipid spillover
comparatively weaker positive correlation. 32 into non-adipose tissues and contributing to dyslipidemia
On the other hand, IGF-1 and -2 and insulin gene and metabolic dysfunction.
expression showed a relevant role in adipose tissue and Studies on gene knockout animal models suggest that
adipogenesis. Adipose tissue serves as a key target for both genes encoding IGFs, their receptors, and insulin play
IGF1 and insulin, with these hormones playing a crucial a crucial role in both regulating growth and controlling
role in the growth and differentiation of both white and adiposity. 43,44 The association between birth weight and
brown adipose tissues. 33,34 Both white and brown adipose polymorphisms in genes related to IGFs and insulin
tissues begin to develop in utero. In human fetuses, adipose expression have been also reported in humans.
tissue first appears between 14 and 24 weeks of gestation Kentistou et al., using exome sequencing data from over
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(early second trimester) as fat lobules without lipid storage. 230,000 participants, identified nine genes influencing birth
The timing varies depending on fetal size, with larger weight. Five out of nine associations (ACVR1C, INHBE,
fetuses developing distinguishable adipocytes earlier than NRK, NYNRIN, PPARG) showed evidence of only fetal-
smaller ones. By the third trimester (28 weeks), adipose genotype effects. IGF1R, PAPPA2, and NOS3 were classified
tissue depots are established, while brown adipose tissue as both fetal- and maternal-acting, with rare variants in all
starts to form around week 20, peaks at week 26, and
stabilizes by week 35. The growth of adipose tissue occurs three genes associating with a lower birth weight in both
through hypertrophy (increase in cell size) and hyperplasia cases. However, among the identified genes, IGF1R and
(increase in cell number, known as adipogenesis). PAPPA2 play a key role in the availability and signaling of
Adipose tissue remains partially expandable throughout IGF in fetal period, while PPARγ, INHBE, and ACVR1C are
life. The number of adipocytes is established during also involved in the regulation of adipose tissue and show
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childhood and adolescence, and remains relatively stable associations with a favorable adipose profile in adults.
throughout adulthood; in humans, approximately 8% of Similarly, mutations in the IGF1R gene that affect the
adipocytes are renewed each year. 35-38 Adipogenesis results function or number of IGF1R can impair intrauterine

Volume 4 Issue 3 (2025) 3 doi: 10.36922/GPD025070011