New Support for CR / CE Synergy Model
Michael has been understandably skeptical of the model of CR / CE synergy I proposed here and discussed further here. This model can be summarized in the rather complicated diagram below. Notice the yellow highlights? These represent aspects of the model that are supported by three papers  published in the last month:
Study  address the significance of SIRT1 for BAT activity. It found that mice genetically deficient in SIRT1 (SIRT1(+ /-)) expressed less SIRT1 in BAT tissue, and this deficit was accompanied by a decrease in mitochondrial DNA expression, reduced expression of UPC1, as well as a decrease in whole body oxygen consumption and an inability for the mice to keep warm during a cold challenge. In short,  suggests that SIRT1 is critical for maintaining proper function of BAT, by boosting mitochondria and UPC1 expression.
Study  looked at the importance of Protein Kinase A (PKA) for promoting BAT activity. Mice genetically programmed to overexpress PKA in adipose tissue were protected from getting obese on a high fat diet, and exhibited increased insulin sensitivity, glucose tolerance and pancreatic β-cell function - a topic many of us are concerned about as a result of the tendency of serious CR to impair glucose tolerance. They also expended more energy without eating more or being more physically active. The mechanism? - you guessed it, increased expression of UCP1 in subcutaneous WAT and BAT, and therefore increased thermogenesis.
In support of the above model, the authors conclude:
These data show that PKA activation is sufficient to induce
changes to a brown-like phenotype in the subcutaneous
WAT and to increase UCP1 expression in BAT.
The authors aren't sure how PKA increases the browning of WAT or increases BAT activity, saying:
Overall, although these studies alter adipose PKA
activity, they do not establish the functional effects of PKA
activity. The importance of our data is that it shows that
activation of PKA alone in adipose tissue is sufficient to induce
resistance to diet-induced obesity.
but there is good evidence that PKA is a mTOR regulator, and that mTOR is critical in the BAT synthesis and the browning of white fat, as we discussed here based on , which linked increased epinephrine (which is upregulated by cold) to elevated PKA activity in adipose tissue, which acted through mTOR1 (specifically the RAPTOR complex) to brown adipose tissue, independent of the insulin/AKT signalling pathway, exactly as shown in the diagram above.
Study  lends further support to the important role mTOR plays in WAT and BAT synthesis, and in insulin sensitivity. Mice that lacked mTOR in adipose tissue had decreased BAT and WAT mass, and were insulin resistant. They conclude:
Our study reveals the critical role of the mTOR signalling pathway in regulating
adipose tissues development, whole-body energy metabolism and insulin sensitivity.
CR reduces insulin and IGF-1 signalling, which may have several good effects wrt inflammation and aging. But it also knocks down the anabolic action of mTOR, which can result in metabolic dysfunction (and impaired glucose tolerance in some of us), and reduced bone and muscle mass. These papers support the idea that cold exposure can overcome these negative effects of CR by activity mTOR via a separate pathway from insulin/IGF-1, involving PKA.
 Zhonghua Yi Xue Za Zhi. 2016 Jun 21;96(23):1859-62. doi:
[Effect of SIRT1 deficiency on function of brown adipose tissue in obese mice].
[Article in Chinese]
Zheng XB(1), Ai HY, Yuan SH, Cao HY, Liang H, Weng JP, Xu F.
(1)Department of Endocrinology and Metabolism, Third Affiliated Hospital, Sun
Yat-sen University, Key Laboratory of Diabetology of Guangdong Province,
Guangzhou 510630, China.
OBJECTIVE: To investigate the effect of silent mating type information regulation
2 homolog 1 (SIRT1) deficiency on function of brown adipose tissue (BAT) in
high-fat diet (HFD)-induced obese mice.
METHODS: Male SIRT1 deficient heterozygous (SIRT1(+ /-)) mice and their wild-type
(WT) littermates were challenged with a HFD diet for 16 weeks to induce obesity
model.Energy metabolic cages were used to measure oxygen consumption and heat
production, and cold tolerance test was to evaluate the adaptive thermogenic
function.With brown fat collected after the diet intervention, determination
techniques were adopted included HE staining for morphologic changes,
immunohistochemical staining and Western blotting for uncoupling protein 1 (UCP1)
expression, quantitative real-time PCR for relative content of mitochondria DNA
RESULTS: Compared to WT controls, SIRT1(+ /-) mice displayed significant
decreases in both oxygen consumption and heat production[(2 681±297) vs (3
017±313) ml·kg(-1)·h(-1,) (19.05±2.40) vs (21.15±2.49) kcal·kg(-1)·h(-1,) both
P<0.05)], as well as an impairment in maintaining their body temperature during
the cold challenge.HE staining revealed the accumulation of larger lipid droplets
in BAT of SIRT1(+ /-) mice, and both immunohistochemical staining and Western
blotting indicated an obvious reduction in expression of UCP1 (P<0.05).
Quantitative real-time PCR showed a significant decrease in the relative mtDNA
content in BAT of SIRT1(+ /-) mice (0.38±0.10 vs 1.00±0.40, P<0.05).
CONCLUSION: SIRT1 deficiency promotes BAT dysfunction, meaning that whitening in
 Am J Physiol Regul Integr Comp Physiol. 2016 Jul 1;311(1):R79-88. doi:
10.1152/ajpregu.00114.2016. Epub 2016 Apr 20.
Protein kinase A induces UCP1 expression in specific adipose depots to increase
energy expenditure and improve metabolic health.
Dickson LM(1), Gandhi S(1), Layden BT(2), Cohen RN(1), Wicksteed B(3).
(1)Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, The
University of Chicago, Chicago, Illinois; (2)Division of Endocrinology,
Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern
University, Chicago, Illinois; and Jesse Brown Veterans Affairs Medical Center,
Chicago, Illinois. (3)Section of Endocrinology, Diabetes and Metabolism,
Department of Medicine, The University of Chicago, Chicago, Illinois; Division of
Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine,
Northwestern University, Chicago, Illinois; and
Adipose tissue PKA has roles in adipogenesis, lipolysis, and mitochondrial
function. PKA transduces the cAMP signal downstream of G protein-coupled
receptors, which are being explored for therapeutic manipulation to reduce
obesity and improve metabolic health. This study aimed to determine the overall
physiological consequences of PKA activation in adipose tissue. Mice expressing
an activated PKA catalytic subunit in adipose tissue (Adipoq-caPKA mice) showed
increased PKA activity in subcutaneous, epididymal, and mesenteric white adipose
tissue (WAT) depots and brown adipose tissue (BAT) compared with controls.
Adipoq-caPKA mice weaned onto a high-fat diet (HFD) or switched to the HFD at 26
wk of age were protected from diet-induced weight gain. Metabolic health was
improved, with enhanced insulin sensitivity, glucose tolerance, and β-cell
function. Adipose tissue health was improved, with smaller adipocyte size and
reduced macrophage engulfment of adipocytes. Using metabolic cages, we found that
Adipoq-caPKA mice were shown to have increased energy expenditure, but no
difference to littermate controls in physical activity or food consumption.
Immunoblotting of adipose tissue showed increased expression of uncoupling
protein-1 (UCP1) in BAT and dramatic UCP1 induction in subcutaneous WAT, but no
induction in the visceral depots. Feeding a HFD increased PKA activity in
epididymal WAT of wild-type mice compared with chow, but did not change PKA
activity in subcutaneous WAT or BAT. This was associated with changes in PKA
regulatory subunit expression. This study shows that adipose tissue PKA activity
is sufficient to increase energy expenditure and indicates that PKA is a
beneficial target in metabolic health.
 Diabetologia. 2016 Jun 13. [Epub ahead of print]
Adipocyte-specific deletion of mTOR inhibits adipose tissue development and causes insulin resistance in mice.
Shan T1,2, Zhang P3,4, Jiang Q3,5, Xiong Y3, Wang Y6, Kuang S7,8.
The in vivo role of mechanistic target of rapamycin (mTOR) in the development and function of adipose tissue, especially brown adipose tissue (BAT), is not well understood. Here, we aimed to assess the effect of mTOR (also known as Mtor) knockout on adipose tissues and systemic energy metabolism.
We generated adipocyte-specific mTOR-knockout mice (Adipoq-mTOR) by crossing adiponectin-Cre (Adipoq-Cre) mice with mTOR flox/flox mice. The mice were then subjected to morphological, physiological (indirect calorimetry, glucose and insulin tolerance tests) and gene expression analyses to determine the role of mTOR in adipose tissues.
We provide in vivo evidence that mTOR is essential for adipose tissue development and growth. Deletion of mTOR decreased the mass of both BAT and white adipose tissues (WAT) and induced browning of WAT. In addition, ablation of mTOR in adipose tissues caused insulin resistance and fatty liver in the Adipoq-mTOR mice. Furthermore, mTOR was required for adipocyte differentiation in vivo and activation of PPARγ ameliorated the differentiation deficiency of the mTOR-null adipocytes.
Our findings demonstrate that mTOR is a critical regulator of adipogenesis and systemic energy metabolism. Our study provides key insights into the role of mTOR in adipose tissues; such knowledge may facilitate the development of novel strategies with which to treat obesity and related metabolic diseases.
Adipose; Browning; Insulin resistance; PPARγ; mTOR
 J Clin Invest. 2016 Mar 28. pii: 83532. doi: 10.1172/JCI83532. [Epub ahead of print]
Activation of mTORC1 is essential for β-adrenergic stimulation of adipose
Liu D, Bordicchia M, Zhang C, Fang H, Wei W, Li JL, Guilherme A, Guntur K, Czech
MP, Collins S.
A classic metabolic concept posits that insulin promotes energy storage and
adipose expansion, while catecholamines stimulate release of adipose energy
stores by hydrolysis of triglycerides through β-adrenergic receptor (βARs) and
protein kinase A (PKA) signaling. Here, we have shown that a key hub in the
insulin signaling pathway, activation of p70 ribosomal S6 kinase (S6K1) through
mTORC1, is also triggered by PKA activation in both mouse and human adipocytes.
Mice with mTORC1 impairment, either through adipocyte-specific deletion of Raptor
or pharmacologic rapamycin treatment, were refractory to the well-known
βAR-dependent increase of uncoupling protein UCP1 expression and expansion of
beige/brite adipocytes (so-called browning) in white adipose tissue (WAT).
Mechanistically, PKA directly phosphorylated mTOR and RAPTOR on unique serine
residues, an effect that was independent of insulin/AKT signaling. Abrogation of
the PKA site within RAPTOR disrupted βAR/mTORC1 activation of S6K1 without
affecting mTORC1 activation by insulin. Conversely, a phosphomimetic RAPTOR
augmented S6K1 activity. Together, these studies reveal a signaling pathway from
βARs and PKA through mTORC1 that is required for adipose browning by
catecholamines and provides potential therapeutic strategies to enhance energy
expenditure and combat metabolic disease.
There will never be peace in the world while there are animals in our bellies.