Sunday, 23 March 2014

Catecholamine resistance in obesity

Inflammation produces catecholamine resistance in obesity via activation of PDE3B by the protein kinases IKK{varepsilon} and TBK1.
Decreased sympathetic activation of adipose tissue due to impaired catecholamine synthesis or sensitivity has been observed in obese patients (Reynisdottir et al., 1994Stallknecht et al., 1997;Horowitz and Klein, 2000Jocken et al., 2008). Obesity is commonly associated with blunted whole-body catecholamine-induced lipolysis (Horowitz and Klein, 2000). This is thought to occur through a number of mechanisms, including leptin resistance (Myers et al., 2010), as well as the reduced expression of β-adrenergic receptors (Reynisdottir et al., 1994) or increased expression of α2-adrenergic receptors (Stich et al., 2002). White adipose tissue and cultured isolated adipocytes from obese human and mouse models exhibit decreased cAMP-stimulated lipolysis and fat oxidation, due to reduced energy expenditure from decreased mitochondrial uncoupling (Yehuda-Shnaidman et al., 2010). This desensitization to adrenergic activation is also a feature of childhood onset obesity (Bougneres et al., 1997Enoksson et al., 2000), and has been observed in adipocytes from first-degree relatives of obese subjects (Hellstrom et al., 1996).

Acute stimulation of white adipocyte respiration by PKA-induced lipolysis.

we present evidence that human white adipocytes can acutely increase aerobic and anaerobic respiration in response to βAR and protein kinase A (PKA)-dependent stimulation of lipolysis.

Lipolysis stimulated by βAR activation or other maneuvers that increase cAMP levels in white adipocytes acutely induces mitochondrial uncoupling and cellular energetics,

Wednesday, 12 March 2014

Insulin hypersecretion in islets from diet-induced obese mice

Insulin hypersecretion in islets from diet-induced hyperinsulinemic obese female mice is associated with several functional adaptations in individual β-cells.


Insulin resistance and hyperinsulinemia are generally associated with obesity. Obese nondiabetic individuals develop a compensatory β-cell response to adjust insulin levels to the increased demand, maintaining euglycemia. Although several studies indicate that this compensation relies on structural changes, the existence of β-cell functional adaptations is incompletely understood. Here, we fed female mice with a high-fat diet (HFD) for 12 weeks. These animals became obese, hyperinsulinemic, insulin-resistant, and mildly glucose-intolerant while fed, and fasting glycemia was comparable in HFD and control mice. Islets from HFD animals exhibited increased β-cell mass and hypertrophy.

Additionally, they had enhanced insulin gene expression and content and augmented glucose-induced insulin secretion. Electrophysiological examination of β-cells from both groups showed no differences in KATP channel open probability and conductance. However, action potentials elicited by glucose had larger amplitude in obese mice. Glucose-induced Ca²⁺ signals in intact islets, in isolated β-cells, and individual β-cells within islets were also increased in HFD mice. Additionally, a higher proportion of glucose-responsive cells was present in obese mice. In contrast, whole-cell Ca²⁺ current densities were similar in both groups.

Capacitance measurements showed that depolarization-evoked exocytosis was enhanced in HFD β-cells compared with controls. Although this augment was not significant when capacitance increases of the whole β-cell population were normalized to cell size, the exocytotic output varied significantly when β-cells were distributed by size ranges. All these findings indicate that β-cell functional adaptations are present in the islet compensatory response to obesity.


Found this in a related link to JJ's 2012 paper on hyperinsulinemia, very interesting that obese islets are programmed to secrete large amounts of insulin for a given amount of glucose?

Is this an "adaption" to insulin resistance? I dont believe so. If we go back to JJ's paper we remember that insulin feed's back positively to beta islets via the autocrine loop to cause growth. Possibly also to cause these morphological changes. I think a reasonable assumption is that anything that causes intense insulin secretion will serve to induce these morphological changes and obesity may follow.