An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice.
Maria RohmMichaela SchäferVictor LaurentBilgen Ekim ÜstünelKatharina NiopekCarolyn AlgireOksana HautzingerTjeerd P SijmonsmaAnnika ZotaDasa MedrikovaNatalia S PellegataMikael RydenAgné KulyteIngrid DahlmanPeter ArnerNatasa PetrovicBarbara CannonEz Zoubir AmriBruce E KempGregory R SteinbergPetra JanovskaJan KopeckyChristian WolfrumMatthias BlüherMauricio Berriel DiazStephan HerzigPublished in: Nature medicine (2016)
Cachexia represents a fatal energy-wasting syndrome in a large number of patients with cancer that mostly results in a pathological loss of skeletal muscle and adipose tissue. Here we show that tumor cell exposure and tumor growth in mice triggered a futile energy-wasting cycle in cultured white adipocytes and white adipose tissue (WAT), respectively. Although uncoupling protein 1 (Ucp1)-dependent thermogenesis was dispensable for tumor-induced body wasting, WAT from cachectic mice and tumor-cell-supernatant-treated adipocytes were consistently characterized by the simultaneous induction of both lipolytic and lipogenic pathways. Paradoxically, this was accompanied by an inactivated AMP-activated protein kinase (Ampk), which is normally activated in peripheral tissues during states of low cellular energy. Ampk inactivation correlated with its degradation and with upregulation of the Ampk-interacting protein Cidea. Therefore, we developed an Ampk-stabilizing peptide, ACIP, which was able to ameliorate WAT wasting in vitro and in vivo by shielding the Cidea-targeted interaction surface on Ampk. Thus, our data establish the Ucp1-independent remodeling of adipocyte lipid homeostasis as a key event in tumor-induced WAT wasting, and we propose the ACIP-dependent preservation of Ampk integrity in the WAT as a concept in future therapies for cachexia.
Keyphrases
- protein kinase
- adipose tissue
- skeletal muscle
- insulin resistance
- high fat diet induced
- high fat diet
- single cell
- high glucose
- cell proliferation
- gene expression
- stem cells
- drug delivery
- cancer therapy
- case report
- papillary thyroid
- squamous cell carcinoma
- deep learning
- fatty acid
- artificial intelligence
- machine learning
- cell free
- current status
- protein protein
- oxidative stress
- nitric oxide