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A detailed analysis of the etiological factors underlying preferential VAT accu­mulation is beyond the scope of this chapter and the topic has already been exten­sively reviewed [2, 25]. Briey, literature supports the role of genetics, age, sex, and steroid hormones. In particular, the contribution of genetics to obesity has been extensively studied in the past decades, by the completion of genome-wide associa­tion studies (GWAS), thereby allowing the identication of a large number of can­didate genes as well as several quantitative trait loci and single-nucleotide polymorphisms (SNP) associated with obesity and body fat distribution [26–29]. Despite the arguably small contribution of genetic predisposition to preferential VAT accumulation and the probable involvement of other factors like epigenetics, gene–gene, and gene–environment interactions [30–33], body fat distribution indis­putably represents a heritable trait [34–37].

Sex also is a well-known determinant of VAT accumulation. It is well recognized that men typically display an android fat distribution prole whereas women prefer­entially accumulate adipose tissue especially in the lower body, dened as a gynoid fat distribution prole [25, 44]. Women have less VAT than men for the same waist circumference [45], a phenomenon that has also been reported when controlling for BMI and total body fat [46]. As mentioned, this sex dimorphism may be attenuated with the occurrence of menopause [42].

78]. Interestingly, visceral adiposity predicted macrophage inltration in both

VAT and SCAT in overweight women [23]. Beyond macrophage inltration, many other immune cell types can be observed in human adipose tissue. In a recent single-cell sequencing analysis performed in subcutaneous and visceral fat, we were able to identify 14 different clusters of immune cells, including 5 different macrophage subtypes, dendritic cells, monocytes, as well as T, B, and natural­killer cells in both compartments [17]. Specically, we identied CD9+ adipose tissue macrophages expressing lipid metabolism genes typical of obesity [17]. The presence of pro- inammatory macrophages and other immune cells com­bined with hypertrophic adipocytes leads to a shift in the adipokines secreted by these cells. Notably, the presence of pro-inammatory cytokines such as TNFα, interleukin 6 and 18 (IL-6, IL-18), as well as an increase in the secretion of leptin concomitant with a reduction in adiponectin can be observed in individuals with obesity [79]. These cytokines are known to affect both lipolysis and insulin sensi­tivity [2], which again stresses the role of impaired fatty acid storage and insulin resistance in adipose tissue dysfunction. Adipose tissue macrophage inltration is not only related to low-grade inammation but also to altered extracellular matrix remodeling. Pericellular brosis resulting from the collagen laments found around the adipocyte has been shown to be positively related to macrophage inl­tration [21]. In addition, pericellular brosis in VAT has been found to be associ­ated with metabolic dysfunction [80]. Adipocyte hypertrophy and altered adipokine secretion may also inhibit angiogenesis and induce hypoxia in adipose tissue [81, 82]. This would then lead to extracellular matrix remodeling, adipose tissue brosis, and chemotaxis of pro-inammatory macrophages and other immune cells [81, 82].

Insulin resistance has long been known to be associated with excess VAT accu­mulation. Analyses from a subgroup of individuals with obesity of the Dallas Heart Study found that volume VAT, rather than SCAT, predicted fasting glucose, insulin, and the homeostatic model assessment of insulin resistance (HOMA-IR) even after adjustment for age, sex, race, menopausal status, and BMI [83]. Interestingly, simi­lar results were reported in the Framingham Heart Study, where the BMI-adjusted odds ratios of insulin resistance in non-diabetic participants for VAT were 2.2 [84]. In spite of the fact that the results of those studies do not allow speculation about the directionality of the association, the large sample size and the consistency of the ndings consolidate the link that exists between excess VAT and insulin resistance. Over the years, the contribution of inammation to insulin resistance in the context of obesity has been emphasized. Indeed, adipose tissue dysfunction and visceral obesity in general have been associated with increased immune cell inltration [23] and inammatory cytokine in adipose tissue [85]. In humans and obese mouse mod­els, insulin resistance has been repeatedly associated with adipose tissue inamma­tion [86]. The contributing role of inammation has been demonstrated in a mouse model lacking the toll-like receptor 4 (TLR4), a cell-surface receptor responsible for the activation of the inammatory cascade in adipose tissue. Mice lacking TLR4 signicantly decreased their secretion of proinammatory cytokines and were par­tially protected from insulin resistance [87].

Not only is obesity associated with insulin resistance, but also with increased NEFA spillover, especially in the postprandial state [88]. This condition is thought to result in part from altered insulin signaling in dysfunctional adipose tissue, lead­ing to a blunted inhibition of basal lipolysis contributing to postprandial plasma NEFA [89]. A second non-exclusive hypothesis is that hypertrophic adipocytes reach their maximal storing capacity, which in turn impedes the appropriate trap­ping of dietary fatty acids in the form of newly synthesized triglycerides [89]. Recently, fatty acid spillover has been shown to be dependent, not on glucose toler­ance, but on total fat mass [90]. The group additionally found that net VAT uptake of dietary fatty acids is higher in glucose-intolerant individuals, upholding the hypothesis that this could be a protective mechanism limiting the effect that increased postprandial NEFA may have on lean organs [90]. Altered inhibition of adipose tissue lipolysis and increased postprandial NEFA spillover are strongly associated with increased ectopic fat accumulation [88] including in lean organs such as the muscle, liver, and the pericardium [5]. Supporting this notion, a recent study found that liver triglyceride levels and brosis were positively and signi­cantly associated with computed tomography-measured VAT area in both T2D and healthy controls [91]. These associations were independent of BMI and WC [91]. The contributing role of VAT excess in the development of insulin resistance and hepatic steatosis has been recently demonstrated in a mouse model where epididy­mal VAT was surgically removed [92]. Compared to controls, high fat-fed mice without VAT had improved insulin sensitivity and signaling in SCAT, muscle, and liver, with signicantly lower triglyceride content in the liver [92].