54 It could be a consequence of altered blood-brain barrier, decreased expression

of LEPRb, or decreased LEPRb signaling via Jak-2-Stat3 due to an imbalance between expression of negative regulators of leptin sensitivity (suppressors of cytokine signaling [SOCS] proteins, protein tyrosine phosphatase 1B [PTP1B] and SH domain phoshatase 2), and of cellular adaptor molecules, such as SH2B1, which facilitates leptin signaling (Fig. 3).54 Another possibility has recently come to light—requirement of Bardet-Biedl proteins for LEPR signaling, inferring a possible Ixazomib molecular weight role of receptor scaffold assembly on neuronal primary cilia.55 Neurons express a primary cilium, on which is assembled a range of receptors involved in development (e.g. Hedgehog), neurohormonal regulation (somatostatin receptor 3) and appetite (melanin-concentrating hormone receptor 1 [MC-1R], and LEPRb).55–59 FDA approved Drug Library order Primary cilia are found on many cells, but not hepatocytes. They may act as sensory

‘cell antennae’, coordinating inter-cellular communications via receptor clustering and signalling.56–58 Bardet-Biedl syndrome (BBS) is the archetypical example of a ciliopathy with profound appetite dysregulation.59 Like children with leptin deficiency or LEPRb mutations,50–53 BBS children are unable to resist the drive to eat, becoming massively obese at an early age, and about half develop T2D and metabolic syndrome.59,60 Multiple mutations of the BBS gene have been described;55,59 in mice, at least four genotypes are associated with defective LEPRb signaling.55,59 Another childhood obesity syndrome that may be ascribed to a ciliopathy is Alström syndrome.61,62 In addition to their respective specific features (skeletal, retinal, renal and hepatobiliary fibrocystic abnormalities, hearing defects and male infertility), BBS and Alström syndrome are both associated with hyperphagic obesity, early onset of insulin resistance, T2D and (best described for Alström syndrome) severe fatty liver disease leading to cirrhosis.63 An animal model of Alström syndrome,

check details the foz/foz mouse (which carries a mutation of the gene for basal body protein, Alms1), develops NAFLD.64 Further, environmental factors affect expression of liver pathology, so that mice fed chow develop only steatosis, whereas those fed a high fat diet develop NASH with fibrosis.64,65 An additional exciting finding is that pre-adipocytes also express primary cilia,66,67 and these play a role in their capacity to differentiate and form triglyceride-storing adipocytes and secrete adiponectin. Further studies should explore whether the problem of restricted adipose expansion in metabolic syndrome and NASH (discussed later) could actually be due to innate properties of pre-adipocytes/adipocyte differentiation rather than ‘adipose exhaustion’.