Adipose Tissue Malfunction Drives Metabolic Dysfunction in Alström Syndrome

Alström syndrome (ALMS) is an extremely rare autosomal recessive disorder caused by mutations in ALMS1 (1,2). ALMSwas first reported in 1959 but has only been recently recognized as a ciliopathy (3,4). Ciliopathies comprise a group of human genetic diseases associated with primary cilia, microtubule-based organelles extending from the cell surface that transduce signals from the extracellular environment. ALMS patients have a spectrum of clinical features including a neurosensory deficit, renal degeneration, cardiomyopathy, and metabolic dysregulation (5,6). The metabolic phenotypes are especially severe, such that nearly all individuals develop childhood obesity within the first 5 years of life, accompanied by insulin resistance, hyperinsulinemia, hyperleptinemia, hyperlipidemia, and, eventually, type 2 diabetes (6,7) (Fig. 1A). Notably, the degree of insulin resistance is much more severe in ALMS patients compared with other genetic causes of obesity such as Bardet-Biedl syndrome, which is a polygenic ciliopathy (7), thus suggesting that ALMS1 mutation affects a crucial part of the machinery that maintains insulin sensitivity. In addition, since excessive accumulation of subcutaneous fat is one of the traits of ALMS, it has been speculated that adipose tissue plays a key role in its metabolic phenotypes, yet little research has been done on the underlying mechanisms. In this issue of Diabetes, Geberhiwot et al. (8) provide evidence that adipose tissue malfunction is a key contributor to ALMS’s systemic insulin resistance. Geberhiwot et al. first cataloged insulin resistance in various tissues, finding that ALMS patients had insulin resistance in adipose tissue, hepatic tissue, and skeletal muscle as compared with sexand age-matched control subjects with a similar BMI. Importantly, the authors noted that subcutaneous fat from ALMS fails to suppress lipolysis in response to insulin, suggesting adipose tissue insulin resistance in ALMS. Moreover, ALMS subcutaneous adipose tissue had larger adipocytes and increased oxidative stress and mitochondrial dysfunction, confirming that the adipose tissue had altered structure and was severely dysfunctional. The authors sought to determine the contribution of adipose tissue to themetabolic dysfunction of ALMS through mouse genetic studies. First, the authors characterized the fat aussie mice, which bear a spontaneous mutation in the Alms1 gene (9) resulting in premature termination of translation. Similar to previous reports (10,11), the authors observed that the fat aussie mice develop severe insulin resistance accompanied by adipocyte hypertrophy. Importantly, the impairment of insulin-stimulated glucose uptake is limited to adipose tissues. The authors created another whole-body Alms1 knockout (Alms) by inserting loxP sites between exon 6 and 7 of Alms1 (Fig. 1B). Much like the fat aussie mice, Alms mice became obese by 3 months of age and had adipocyte hypertrophy, hyperglycemia, glucose intolerance, and insulin resistance (Fig. 1B). Critically, these metabolic phenotypes were largely reversed by reintroducingAlms1 into adipose tissue, by way of crossing Alms1 with adiposespecific adiponectin-Cre mice (Fig. 1B). Lastly, the authors performed ALMS1 loss-of-function studies in human adipocytes, finding that ALMS1 silencing inhibited insulinstimulated glucose uptake, which provides evidence for a cell autonomous role for ALMS1 in adipocyte insulin resistance. Overall, the authors provide convincing evidence that adipose tissue is the main driver for metabolic dysregulation in ALMS syndrome. A major strength of the work is the rescue of knockout mice with adipose-specific Alms1 expression. The finding thatmice aremetabolically normal when they are deficient in Alms1 in every tissue but adipose provides powerful evidence supporting the conclusion that adipose tissue is a key player in the metabolic phenotypes of ALMS. Despite that, we still lack detailed mechanistic insight into how ALMS1 loss of function causes obesity and adipose dysfunction. ALMS has been recognized as a ciliopathy, as available data suggest that ALMS1 is involved in primary cilium function, particularly intracellular trafficking and protein transport (4,7,12). ALMS1 may participate in the trafficking of proteins from the Golgi apparatus to other parts of