Novel Mediators of the Lipodystrophy and Metabolic Consequences of Cushing's Disease
Condition: Cushing's Syndrome
MeSH terms: ACTH-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion; Lipodystrophy; Cushing Syndrome
Study type: Observational

Summary: 
      This proposal will evaluate the glucocorticoid mediated changes in body fat distribution and
      metabolism that occur in patients with Cushing's disease. The objective is to identify the
      mechanisms that influence both the accumulation of lipodystrophic fat and also the changes in
      energy expenditure and metabolism that accompany them. The study is designed to determine if
      the high cortisol and AgRP levels in the blood of people living with Cushing's syndrome,
      either from taking steroid medications or from tumors, impact body fat and metabolism by
      turning off brown fat, which is a type of fat that increases one's metabolism.
    

Detailed description: 
      Cushing's disease (CD) is a disorder of chronic glucocorticoid (GC) excess that gives rise to
      a constellation of metabolic comorbidities and to a distinct lipodystrophic body habitus
      characterized by central adiposity, extremity wasting, and the accumulation of
      supraclavicular (SC) and dorsocervical (DC) fat in the region where human brown and beige
      adipose tissue is known to be concentrated. In spite of the recognized thermogenic capacity
      of select cervical adipocytes, the potential impact of lipomatous alterations in this depot
      on energy balance and metabolism in CD is unknown. To our knowledge, the "buffalo hump" and
      the supraclavicular fat pads - which are a sensitive physical finding for CD, have never been
      phenotypically characterized and the mechanisms underlying the GC mediated development of fat
      in these depots and the associated metabolic complications have not been explored in humans.
      The proposed research will advance our understanding of Cushing's lipodystrophy and its
      metabolic complications. Furthermore, it may lead to the identification of novel mediators
      and targetable pathways to attenuate the adverse effects of hypercortisolism on body
      composition and metabolism in CD, as well as in the significant population of patients
      treated with chronic GCs for an array of other clinical conditions. These findings may have
      important implications not only for those with Cushing's disease, but for the millions of
      Americans who are treated with chronic glucocorticoids for an array of clinical conditions.
    

Intervention name(s): Treatment of Cushing's
Intervention type(s): Procedure
Intervention description(s): Surgical resection of ACTH-secreting tumor to achieve cure of hypercortisolism
Other intervention name(s): Medical treatment of hypercortisolism
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients with ACTH-dependent Cushing's syndrome
      
Biospecimen description: 
      Subjects will undergo 4mm punch biopsies of the SC, DC, and subcutaneous abdominal fat pads
      under local anesthesia (lidocaine). Biopsies will be performed by an interventional
      radiologist or surgeon. Specimens will be prepared for histologic analysis and for
      immunohistochemical analysis for brown and white adipose tissue markers.
    
Keywords: Glucocorticoids