Browning of white adipose tissue by melatonin

There are two distinct types of adipose tissue which have different functions within the body, white (WAT) and brown (BAT). Browning of WAT occurs with increases in the WAT sympathetic nervous system (SNS) drive. In this regard we previously reported that melatonin (MEL) stimulation of MEL receptor 1A (MEL1a) within the SNS outflow to the WAT might be implicated in a naturally-occurring reversal of obesity (by ~30% of total body fat). Therefore, in this study we tested the hypothesis that MEL causes browning of WAT through the stimulation of SNS drive to WAT. This was done by comparing specific browning and lipolytic markers in WAT following 10 weeks of MEL treatment, short day housing (SD), and long day housing with saline injections (LD+VEH). Browning effects of a 5 day treatment of a β3-adrenergeric (β3 AR), CL 316, 243, were also measured. We found that CL 316, 243, MEL treatment, and SD housing had increased expressions of browning markers within WAT and lipolytic activity in MEL treated animals was increased in specific WAT

Pmch-deficiency in rats is associated with normal adipocyte differentiation and lower sympathetic adipose drive.

The orexigenic neuropeptide melanin-concentrating hormone (MCH), a product of Pmch, is an important mediator of energy homeostasis. Pmch-deficient rodents are lean and smaller, characterized by lower food intake, body-, and fat mass. Pmch is expressed in hypothalamic neurons that ultimately are components in the sympathetic nervous system (SNS) drive to white and interscapular brown adipose tissue (WAT, iBAT, respectively). MCH binds to MCH receptor 1 (MCH1R), which is present on adipocytes. Currently it is unknown if Pmch-ablation changes adipocyte differentiation or sympathetic adipose drive. Using Pmch-deficient and wild-type rats on a standard low-fat diet, we analyzed dorsal subcutaneous and perirenal WAT mass and adipocyte morphology (size and number) throughout development, and indices of sympathetic activation in WAT and iBAT during adulthood. Moreover, using an in vitro approach we investigated the ability of MCH to modulate 3T3-L1 adipocyte differentiation. Pmch-deficiency decreased dorsal subcutaneous and perirenal WAT mass by reducing adipocyte size, but not number. In line with this, in vitro 3T3-L1 adipocyte differentiation was unaffected by MCH. Finally, adult Pmch-deficient rats had lower norepinephrine turnover (an index of sympathetic adipose drive) in WAT and iBAT than wild-type rats. Collectively, our data indicate that MCH/MCH1R-pathway does not modify adipocyte differentiation, whereas Pmch-deficiency in laboratory rats lowers adiposity throughout development and sympathetic adipose drive during adulthood

Beta-adrenergic receptors are critical for weight loss but not for other metabolic adaptations to the consumption of a ketogenic diet in male mice

Objective: We have previously shown that the consumption of a low-carbohydrate ketogenic diet (KD) by mice leads to a distinct physiologic state associated with weight loss, increased metabolic rate, and improved insulin sensitivity [1]. Furthermore, we identified fibroblast growth factor 21 (FGF21) as a necessary mediator of the changes, as mice lacking FGF21 fed KD gain rather than lose weight [2]. FGF21 activates the sympathetic nervous system (SNS) [3], which is a key regulator of metabolic rate. Thus, we considered that the SNS may play a role in mediating the metabolic adaption to ketosis. Methods: To test this hypothesis, we measured the response of mice lacking all three β-adrenergic receptors (β-less mice) to KD feeding. Results: In contrast to wild-type (WT) controls, β-less mice gained weight, increased adipose tissue depots mass, and did not increase energy expenditure when consuming KD. Remarkably, despite weight-gain, β-less mice were insulin sensitive. KD-induced changes in hepatic gene expression of β-less mice were similar to those seen in WT controls eating KD. Expression of FGF21 mRNA rose over 60-fold in both WT and β-less mice fed KD, and corresponding circulating FGF21 levels were 12.5 ng/ml in KD-fed wild type controls and 35.5 ng/ml in KD-fed β-less mice. Conclusions: The response of β-less mice distinguishes at least two distinct categories of physiologic effects in mice consuming KD. In the liver, KD regulates peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways through an action of FGF21 independent of the SNS and beta-adrenergic receptors. In sharp contrast, induction of interscapular brown adipose tissue (BAT) and increased energy expenditure absolutely require SNS signals involving action on one or more β-adrenergic receptors. In this way, the key metabolic actions of FGF21 in response to KD have diverse effector mechanisms

<i>Pmch</i>-deficiency lowers body- and fat mass during development.

<p>(<b>A</b>) Body mass (BM), (<b>B</b>) dWAT mass, (<b>C</b>) pWAT mass, and (<b>D</b>) serum leptin concentrations in WT and HOM rats (n = 8–15/group) at postnatal (PND) days 40, 60, and 120, and (<b>E</b>) body mass and (<b>F</b>) iBAT mass in WT and HOM rats (n = 15–19/group) at PND 147. *<i>P</i><0.05 vs WT.</p

MCH does not modify <i>in vitro</i> 3T3-L1 cell differentiation.

<p>(<b>A</b>) 3T3-L1 cell differentiation after 7-day administration of 1 nM, 10 nM, 100 nM, 1 <i>µ</i>M, or 10 <i>µ</i>M MCH as visualized by Oil-red-O staining (x20 magnification). (<b>B</b>) Western blot analysis for FABP4 (also known as aP2). Tubulin was used to control for input. Assays were performed in triplicate.</p

<i>Pmch</i>-deficiency lowers sympathetic adipose drive.

<p>(<b>A</b>) NETO in dWAT, pWAT, eWAT, and iBAT of WT and HOM rats at PND 153 (n = 8–11/group). (<b>B</b>) Relative mRNA expression of Uncoupling Protein 1 (<i>Ucp1</i>) and β3-adrenoceptor (<i>Adrb3</i>) in iBAT of WT and HOM rats at PND 40 (left) and 90 (right) (n = 5–6/group). *<i>P</i><0.05 vs WT.</p