Obesity is associated with a state of chronic low-grade inflammation and the present invention establishes that adipose-resident natural killer T (NKT) cells attenuate inflammation in adipose tissue and improves systemic glucose homeostasis in mice at different stages of obesity. Accordingly, the present invention provides methods of treating type-2 diabetes or those at risk for type-2 diabetes using activators of adipose-resident NKT cells. Such activators include particular glycolipids (e.g., a-galactosylceramide and its analogs other than sulfated analogs) and cytokines that promote M2 macrophage polarization. The invention also includes methods to screen for activators of adipose-resident NKT cells.

Qi; Ling

Ji; Yewei

Cornell University

Method to screen for an activator of adipose-resident NK cells

The present invention provides novel piperidine derivatives of formula (I), ##STR00001## wherein R represents a substituted benzyl group, which are useful as inhibitors of glucosylceramide synthase (GCS). The compounds of the Invention are useful for treating various glycolipid storage diseases, such as Gaucher's disease, Sandhoff's disease, Tay-Schs disease, Fabry disease, and GM1 gangliosidosis; glycolipid accumulation disorders, such as Niemann-Pick disease, mucopolysaccharidoses, mucolipidosis type IV and .alpha.-mannosidosis; various cancers that involve abnormal glycolipid synthesis; and various infectious diseases that involve cell surface glycolipids as receptors for the infectious organisms or for their toxins; as well as a variety of other disorders involving glycolipid synthesis, including neuronal disorders, inflammatory diseases, obesity, and the like.

Actelion Pharmaceuticals Ltd.

2-Hydroxymethyl-3,4,5-trihydroxy-1-benzilpiperidine derivatives as inhibitors of glucosylceramide

The present invention relates to the compound 3,4,5-piperidinetriol, 2-(hydroxymethyl)-1-[(4-(pentyloxy)phenyl)methyl]-, (2S,3S,4R,5S), or a pharmaceutically acceptable salt or prodrug thereof, which is useful as an inhibitor of glucosylceramide synthase. The compounds of the Invention are useful for treating various glycolipid storage diseases, such as Gaucher's disease, Sandhoff's disease, Tay-Sacs disease, Fabry disease, and GM1 gangliosidosis; glycolipid accumulation disorders, such as Niemann-Pick disease, mucopolysaccharidoses, mucolipidosis type IV and .alpha.-mannosidosis; various cancers that involve abnormal glycolipid synthesis; and various infectious diseases that involve cell surface glycolipids as receptors for the infectious organisms or for their toxins; as well as a variety of other disorders involving glycolipid synthesis, including neuronal disorders, inflammatory diseases, obesity, and the like.

glycolipid/obesity

Method to screen for an activator of adipose-resident NK cells

2-Hydroxymethyl-3,4,5-trihydroxy-1-benzilpiperidine derivatives as inhibitors of glucosylceramide

2-hydroxymethy1-3,4,5-trihydroxy-1-(4-pentyloxybenzyl) piperidine as glucosylceramide synthase (Gcs) inhibitor

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