Lack of AKT in adipocytes causes severe lipodystrophy.

OBJECTIVE: Adipose depot mass is tightly regulated to maintain energy homeostasis. AKT is a critical kinase in the insulin-signaling cascade that is required for the process of adipogenesis in vitro. However, the role of AKT in the maintenance and/or function of mature adipocytes in vivo had not been examined. METHODS: To study this, we deleted Akt1 and Akt2 in adipocytes of mice using the AdipoQ-Cre driver. RESULTS: Strikingly, mice lacking adipocyte AKT were severely lipodystrophic, having dramatically reduced gonadal adipose and no discernible subcutaneous or brown adipose tissue. As a result, these mice developed severe insulin resistance accompanied by fatty liver, hepatomegaly and with enlarged islets of Langerhans. CONCLUSIONS: These data reveal the critical role of adipocyte AKT and insulin signaling for maintaining adipose tissue mass.

The role of mouse Akt2 in insulin-dependent suppression of adipocyte lipolysis in vivo.

AIM/HYPOTHESIS: The release of fatty acids from adipocytes, i.e. lipolysis, is maintained under tight control, primarily by the opposing actions of catecholamines and insulin. A widely accepted model is that insulin antagonises catecholamine-dependent lipolysis through phosphorylation and activation of cAMP phosphodiesterase 3B (PDE3B) by the serine-threonine protein kinase Akt (protein kinase B). Recently, this hypothesis has been challenged, as in cultured adipocytes insulin appears, under some conditions, to suppress lipolysis independently of Akt. METHODS: To address the requirement for Akt2, the predominant isoform expressed in classic insulin target tissues, in the suppression of fatty acid release in vivo, we assessed lipolysis in mice lacking Akt2. RESULTS: In the fed state and following an oral glucose challenge, Akt2 null mice were glucose intolerant and hyperinsulinaemic, but nonetheless exhibited normal serum NEFA and glycerol levels, suggestive of normal suppression of lipolysis. Furthermore, insulin partially inhibited lipolysis in Akt2 null mice during an insulin tolerance test (ITT) and hyperinsulinaemic-euglycaemic clamp, respectively. In support of these in vivo observations, insulin antagonised catecholamine-induced lipolysis in primary brown fat adipocytes from Akt2-deficient mice. CONCLUSIONS/INTERPRETATION: These data suggest that suppression of lipolysis by insulin in hyperinsulinaemic states can take place in the absence of Akt2.

The MTAP-CDKN2A locus confers susceptibility to a naturally occurring canine cancer.

BACKGROUND: Advantages offered by canine population substructure, combined with clinical presentations similar to human disorders, makes the dog an attractive system for studies of cancer genetics. Cancers that have been difficult to study in human families or populations are of particular interest. Histiocytic sarcoma is a rare and poorly understood neoplasm in humans that occurs in 15% to 25% of Bernese Mountain Dogs (BMD). METHODS: Genomic DNA was collected from affected and unaffected BMD in North America and Europe. Both independent and combined genome-wide association studies (GWAS) were used to identify cancer-associated loci. Fine mapping and sequencing narrowed the primary locus to a single gene region. RESULTS: Both populations shared the same primary locus, which features a single haplotype spanning MTAP and part of CDKN2A and is present in 96% of affected BMD. The haplotype is within the region homologous to human chromosome 9p21, which has been implicated in several types of cancer. CONCLUSIONS: We present the first GWAS for histiocytic sarcoma in any species. The data identify an associated haplotype in the highly cited tumor suppressor locus near CDKN2A. These data show the power of studying distinctive malignancies in highly predisposed dog breeds. IMPACT: Here, we establish a naturally occurring model of cancer susceptibility due to CDKN2 dysregulation, thus providing insight about this cancer-associated, complex, and poorly understood genomic region.

Man's best friend becomes biology's best in show: genome analyses in the domestic dog.

In the last five years, canine genetics has gone from map construction to complex disease deconstruction. The availability of a draft canine genome sequence, dense marker chips, and an understanding of the genome architecture has changed the types of studies canine geneticists can undertake. There is now a clear recognition that the dog system offers the opportunity to understand the genetics of both simple and complex traits, including those associated with morphology, disease susceptibility, and behavior. In this review, we summarize recent findings regarding canine domestication and review new information on the organization of the canine genome. We discuss studies aimed at finding genes controlling morphological phenotypes and provide examples of the way such paradigms may be applied to studies of behavior. We also discuss the many ways in which the dog has illuminated our understanding of human disease and conclude with a discussion on where the field is likely headed in the next five years.

Leading the way: canine models of genomics and disease.

In recent years Canis familiaris, the domestic dog, has drawn considerable attention as a system in which to investigate the genetics of disease susceptibility, morphology and behavior. Because dogs show remarkable intrabreed homogeneity, coupled with striking interbreed heterogeneity, the dog offers unique opportunities to understand the genetic underpinnings of natural variation in mammals, a portion of which is disease susceptibility. In this review, we highlight the unique features of the dog, such as population diversity and breed structure, that make it particularly amenable to genetic studies. We highlight recent advances in understanding the architecture of the dog genome, which propel the system to the forefront of consideration when selecting a system for disease gene studies. The most notable benefit of using the dog for genetic studies is that dogs get many of the same diseases as humans, with a similar frequency, and the same genetic factors are often involved. We discuss two approaches for localizing disease genes in the dog and provide examples of ongoing studies.