*2.6. Obesity*

Dysregulation of primary cilia in the central nervous system and peripheral tissues is associated with obesity, which often accompanies ciliopathies, such as BBS and Alström syndrome [49,50,80,81]. Obesity results from an excessive calorie intake relative to energy expenditure. In response to food intake, leptin is secreted from adipocytes and binds to receptors located in the primary cilia of anorexigenic and orexigenic neurons in the hypothalamus, resulting in increased and decreased expression of the anorexigenic peptide pro-opiomelanocortin and the orexigenic peptide Agouti-related peptide, respectively [82–84]. Genes associated with BBS and Alström syndrome regulate primary cilia in these hypothalamic neurons, and mutation of these genes can lead to obesity by failing to suppress the appetite through primary cilia-mediated leptin signaling [50].

Another contributing factor in obesity is elevated adipogenesis, resulting in an increased abundance of adipocytes [85]. Primary cilia are present in differentiating preadipocytes and play critical roles in adipogenesis [86]. Impairment of primary cilia in preadipocytes' knockdown of BBS proteins (BBS10 and BBS12) stimulates adipogenesis by activation of the glycogen synthase kinase 3 pathway and nuclear accumulation of peroxisome proliferator-activated receptor γ [86]. Knockdown of BBS12 in human mesenchymal stem cells also impairs ciliogenesis and enhances adipogenesis [87]. In contrast, knockdown of intraflagellar transport 88 in preadipocytes or mesenchymal stem cells inhibits adipogenesis by impairing the localization of insulin-like growth factor-1 receptors in primary cilia [88,89]. The precise mechanisms by which primary cilia regulate adipogenesis remain to be fully elucidated.
