Editors' ChoiceCancer

Preventing white fat from wasting away

Sci. Signal.  18 Oct 2016:
Vol. 9, Issue 450, pp. ec245
DOI: 10.1126/scisignal.aal2176

Some tumors cause progressive wasting of adipose tissue, then of skeletal muscle. This condition, called cancer-associated cachexia (cancer cachexia), decreases quality of life for cancer patients and predicts poor survival. Rohm et al. investigated the metabolic mechanisms underlying white adipose tissue wasting in cancer cachexia. Exposure of mouse 3T3-L1 white adipocytes to noncell conditioned medium or medium conditioned by cell lines that do not cause cachexia did not alter lipolysis [as assessed by the release of nonesterified fatty acids (NEFAs)] or lipogenesis. In contrast, both lipolysis and lipogenesis were increased, and maximal respiratory capacity and ATP concentrations were reduced in 3T3-L1 adipocytes exposed to medium conditioned by cell lines derived from cachexia-inducing tumors, including C26 colon cancer cells. Similarly, serum from mice bearing C26-derived tumors also increased NEFA release and lipogenesis when applied to 3T3-L1 adipocytes. In accordance with the increased lipolysis and lipogenesis, the extent of phosphorylation at inhibitory sites in hormone-sensitive lipase (HSL) and the lipogenic enzyme acetyl-coenzyme A carboxylase (ACC) was lower in 3T3-L1 adipocytes exposed to C26 cell-conditioned medium than in adipocytes exposed to noncell conditioned medium. The inhibitory sites in both HSL and ACC can be phosphorylated by AMP-activated protein kinase (AMPK), which is an energy sensor that is normally activated by low ATP concentrations. However, AMPK abundance and activity and HSL and ACC phosphorylation at inhibitory sites were reduced in the white adipose tissue of mice with C26-derived tumors. Reconstitution of a constitutively active form of AMPK in 3T3-L1 adipocytes partially prevented lipolysis induced by exposure to serum from C26-derived tumor-bearing mice. AMPK undergoes degradation when the β subunit of AMPK interacts with Cidea, a lipid droplet–associated protein that is abundant in brown adipose tissue but can also be detected in white adipose tissue. Cidea suppresses the energy-burning function of brown adipose tissue. Cidea abundance was increased in white adipose tissue at the onset of cancer cachexia in mice, and CIDEA expression in white adipose depots was greater in cachectic patients than in noncachectic patients. The authors developed a peptide that they called ACIP to block the interaction between Cidea and AMPK. ACIP expression in primary mouse white adipocytes increased the interaction of the AMPK α and β subunits, increased the phosphorylation of HSL and ACC at inhibitory sites, and prevented NEFA release upon exposure to serum from C26-derived tumor-bearing mice. Injection of adeno-associated virus encoding ACIP either into white adipose depots or systemically prevented implanted C26-derived tumors from inducing white adipose tissue wasting, disrupting the interaction between the AMPK α and β subunits, and suppressing the phosphorylation of HSL and ACC at inhibitory sites. Thus, stabilizing AMPK selectively in white adipose tissue may prevent tumor-induced cachexia and improve quality of life for cancer patients.

M. Rohm, M. Schäfer, V. Laurent, B. E. Üstünel, K. Niopek, C. Algire, O. Hautzinger, T. P. Sijmonsma, A. Zota, D. Medrikova, N. S. Pellegata, M. Ryden, A. Kulyte, I. Dahlman, P. Arner, N. Petrovic, B. Cannon, E.-Z. Amri, B. E. Kemp, G. R. Steinberg, P. Janovska, J. Kopecky, C. Wolfrum, M. Blüher, M. B. Diaz, S. Herzig, An AMP-activated protein kinase–stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice. Nat. Med. 22, 1120–1130 (2016). [PubMed]

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