Substances tested

Anti-lipolytic. Insulin activates PDE3B in adipocytes through Akt, lowering cAMP and shutting down the PKA-driven lipolytic cascade. Insulin-induced phosphorylation and activation of PDE3B in 3T3-L1 adipocytes was blocked by dominant-negative Akt; the S273A mutant was neither phosphorylated by insulin nor activated in adipocytes, placing Ser273 as the Akt site.

Stimulates glucose transport by translocating transporters from an intracellular pool to the plasma membrane rather than by activating transporters already at the surface. The founding observation for insulin-regulated GLUT4 trafficking in the fat cell.

Activates human brown adipose tissue. A single oral dose raised BAT metabolic activity on 18F-FDG PET/CT in all twelve subjects (p = 0.001) and increased resting metabolic rate by 203 plus or minus 40 kcal per day, a 13 percent rise (p = 0.001). BAT activity significantly predicted the change in resting metabolic rate.

Thiazolidinediones are potent and selective activators of PPARgamma. BRL49653 binds PPARgamma with a dissociation constant near 40 nM. Treating pluripotent C3H10T1/2 stem cells with BRL49653 drove efficient differentiation into adipocytes, linking the antidiabetic drug class directly to the adipogenic master regulator.

Forced expression of PPARgamma2 in fibroblasts is sufficient to convert them into adipocytes. Establishes PPARgamma as the master transcriptional regulator of adipogenesis and explains why a PPARgamma ligand is an adipogenic drug.

Anti-lipolytic. The orphan receptor PUMA-G/HM74 is highly expressed in adipose tissue and is a nicotinic acid receptor; binding lowers cAMP through Gi. In PUMA-G null mice the nicotinic acid induced fall in plasma free fatty acids and triglyceride was abolished, showing the receptor mediates the anti-lipolytic effect in vivo.

Blocks the rate-limiting first step of lipolysis. Atglistatin is selective for ATGL and reduces fatty acid mobilization in vitro and in vivo. The proof that the rate-limiting lipase is druggable.

ATGL performs the rate-limiting hydrolysis of triacylglycerol to diacylglycerol plus a fatty acid. ATGL deletion causes massive lipid accumulation in adipose and cardiac tissue, confirming it as the dominant route by which the fat cell releases its stored lipid.

A lipolytic pathway in human fat that does not use cAMP. In isolated human fat cells ANP and BNP stimulated lipolysis as strongly as isoproterenol, with potency ANP greater than BNP greater than CNP; microdialysis confirmed the effect in abdominal subcutaneous adipose tissue. Blocking or activating PDE3B and inhibiting adenylyl cyclase altered the isoproterenol response but not the ANP response, establishing a cGMP-dependent and cAMP-independent route.

Pro-adipogenic on human preadipocytes. In serum-free chemically defined medium, cortisol produced potent dose-dependent stimulation of adipose differentiation of human subcutaneous stromal-vascular cells and could be replaced by dexamethasone, partly by aldosterone, but not by sex steroids. Differentiation extent fell markedly with donor age, up to 70 percent from young adults versus 5 to 10 percent from the oldest.

Thermogenic. Chronic treatment of young rats on a high-fat diet raised body temperature and 24 hour energy expenditure mainly through resting metabolic rate, with food intake unchanged and carcass fat reduced. Interscapular brown adipose tissue was markedly hypertrophied with three to fourfold increases in uncoupling protein and cytochrome oxidase content; mitochondria were smaller with unchanged UCP per mitochondrion.

Drives browning of white adipose tissue. FGF21-deficient mice adapt poorly to chronic cold with diminished browning of white fat. Adipose-derived FGF21 acts in an autocrine and paracrine manner to raise UCP1 and other thermogenic genes, at least partly by increasing adipose PGC-1alpha protein independently of its mRNA.

The reference lipolytic stimulus in human fat, and the paper that qualifies the beta-3 story in humans. Beta-3 mRNA is 20 percent of total beta-adrenoceptor transcripts in human subcutaneous adipocytes, but only CGP12177 among beta-3 agonists produced lipolysis, with 4 to 5 fold lower efficacy than isoprenaline. Nadolol, a beta-1 and beta-2 antagonist, blocked isoprenaline-stimulated lipolysis, showing isoprenaline acts solely through beta-1 and beta-2 in these cells and that human beta-3 contributes little.

Stimulates brown adipose thermogenesis and browning, but centrally. Central injection of liraglutide in mice stimulated BAT thermogenesis and adipocyte browning independent of nutrient intake; the mechanism maps to the hypothalamic ventromedial nucleus, and AMPK activation there was sufficient to blunt both effects. In a one year study of obese type 2 diabetic patients, exenatide and liraglutide both increased energy expenditure. The adipose effect in this paper is centrally mediated, not a direct adipocyte action.

Reproduces adiponectin signalling with an oral small molecule. AdipoRon bound both AdipoR1 and AdipoR2 in vitro and activated AMPK and PPAR-alpha, ameliorating insulin resistance and glucose intolerance in high-fat-fed mice; the effects were completely abolished in AdipoR1 and AdipoR2 double-knockout mice. It also ameliorated diabetes in db/db mice and prolonged their shortened lifespan on a high-fat diet. The abstract reports the tissue effects in muscle and liver; adiponectin itself is the adipocyte-derived ligand.

Browning agent released by muscle. Muscle PGC1-alpha increases FNDC5, which is cleaved and secreted as irisin; irisin acts on white adipose cells in culture and in vivo to stimulate UCP1 and a broad brown-fat-like gene program. Irisin is induced by exercise in mice and humans, and mildly raised blood irisin increased energy expenditure in mice without changes in movement or food intake, improving obesity and glucose homeostasis.

Restrains lipolysis. Metformin attenuated TNF-alpha mediated lipolysis by suppressing ERK1/2 phosphorylation and reversing perilipin downregulation, and also restricted the acute lipolytic response to isoproterenol. High glucose raised basal glycerol release and enhanced both TNF-alpha and isoproterenol stimulated lipolysis; metformin suppressed basal and high-glucose-enhanced lipolysis. The commonly cited metformin to AMPK link is not supported by this abstract.

Causes insulin resistance from within the fat cell. Adipose tissue expresses TNF-alpha, expression is elevated in obesity, and neutralising it in obese rodents restores insulin-stimulated glucose uptake. Establishes adipose TNF-alpha as a causal driver of obesity-linked insulin resistance and the fat cell as an endocrine organ acting on whole-body metabolism.

The endpoint of adrenergic stimulation in brown fat. UCP1 in brown adipose mitochondria dissipates the proton gradient as heat rather than driving ATP synthesis; this is the bioenergetic basis of adrenergically driven non-shivering thermogenesis and the reason a beta-3 agonist raises metabolic rate.

Pro-lipolytic directly on isolated human subcutaneous adipocytes. GIP alone increased glycerol release by 13 percent compared with basal. The effect was not related to age or BMI. Higher adipose GIPR mRNA expression correlated with greater glycerol release after GIP stimulation.

Pro-lipolytic, stronger effect than GIP alone. The triagonist raised glycerol release by 28 percent in isolated human SAT adipocytes, compared with 13 percent for GIP alone, suggesting synergistic receptor engagement. Neither GLP-1 nor glucagon alone reproduced the effect, indicating GIP receptor activation drives the lipolytic component.

No direct lipolytic effect on isolated human subcutaneous adipocytes. In the same assay where GIP raised glycerol by 13 percent and the triagonist by 28 percent, GLP-1 alone produced no significant change. GLP-1 receptor agonist weight-loss effects operate through other mechanisms, not direct adipocyte lipolysis.

No direct lipolytic effect on isolated human subcutaneous adipocytes. Glucagon alone produced no significant change in glycerol release, contrasting with its well-documented pro-lipolytic action in rodent adipocytes and suggesting depot-specific and species-specific receptor expression differences.

Remodels adipose tissue in type 2 diabetes beyond glycaemic control. Evidence synthesised in a review indicates semaglutide shifts adipose tissue from a pro-inflammatory, lipid-storing phenotype toward a more oxidative and insulin-sensitive state: effects include regulation of adipocyte lipolysis and lipid metabolism, enhancement of mitochondrial biogenesis and oxidative capacity, induction of beige adipocyte programming, modulation of adipokine and cytokine secretion, and attenuation of adipose fibrosis.

Induces adipocyte differentiation in vivo and improves insulin action. In obese Zucker (fa/fa) rats, pioglitazone markedly improved insulin action but doubled weight gain after 4 weeks. It induced a large increase in glucose utilisation in adipose tissue and stimulated lipid-metabolism gene expression (GLUT, fatty acid synthase, PEPCK) while decreasing ob gene expression. Histology showed a large increase in small adipocytes in retroperitoneal fat, indicating enhanced adipocyte differentiation in vivo alongside direct effects on mature adipocyte gene expression.

Anti-lipolytic via PKB/Akt-driven PDE3B activation in primary human subcutaneous adipocytes. In adipocytes from non-diabetic and type 2 diabetic women, insulin activated PKB/Akt and stimulated PDE3B, reducing cAMP and suppressing isoproterenol-stimulated lipolysis. The magnitude of anti-lipolytic effect was similar between non-diabetic and diabetic donors, demonstrating that the acute insulin-PDE3B axis is largely preserved in type 2 diabetes.

Anti-lipolytic via EP3 receptor. Sulprostone, enprostil and 16,16-dimethyl PGE2 were all potent inhibitors of IBMX-stimulated lipolysis in rat isolated adipocytes. The EP1-selective blocker AH6809 had no effect on the anti-lipolytic response to PGE2 or sulprostone, establishing EP3 as the principal mediating subtype.

Anti-lipolytic. Endogenous adenosine tonically activates A1ARs in adipose tissue. A1AR activation reduces adenylate cyclase activity and cAMP, inhibiting lipolysis and lowering circulating free fatty acids. A1AR knockout mice and selective agonists have confirmed the receptor as the principal adenosinergic brake on adipocyte lipolysis; reduction of circulating free fatty acids is proposed as a mechanism for improving insulin resistance.

Drives beige fat development. Eosinophils are the major source of IL-4 and IL-13 in white adipose tissue; type 2 cytokine signalling in adipose macrophages is required for development of functional UCP1-positive beige fat in response to cold. The mechanism defines an eosinophil-macrophage-adipocyte axis that converts white to thermogenic beige fat.